AAN Annual Meeting

SAN DIEGO – Thinner multiple sclerosis patients may be at higher risk for natalizumab-induced progressive multifocal leukoencephalopathy, according to researchers from the Rocky Mountain Multiple Sclerosis Research Group in Salt Lake City.

The risk may derive from the drug’s higher mean plasma concentrations and the greater saturation of lymphocyte receptors in such patients, lead investigator Dr. John Foley suggested.

He and his team reviewed 38 natalizumab (Tysabri)-induced progressive multifocal leukoencephalopathy (PML) cases – 11.5% of the current global total – and found that 24 of the patients were 70 kg or less and 29 were 80 kg or less. The median weight of the PML patients was 64 kg, substantially lower than the weight of the average MS patient, at least at the Rocky Mountain clinic.

At 60 kg or less, "there is a striking elevation in PML cases. [The] incidence definitely trends towards patients with lower body weights," said Dr. Foley, founder of the clinic.

To further explore the issue, his team also analyzed clinical data from 301 of its own natalizumab patients, plus data from 826 patients in the Swedish Natalizumab Registry, 799 patients from phase III trials, and patients from other sources.

In doing so, they also found that patients weighing less than 75 kg tend to develop higher plasma concentrations of the monoclonal antibody over time and are more likely to saturate 95% or more of the lymphocyte receptors that natalizumab targets, exceeding the saturation goal of about 85%.

Patients who weighed no more than 70 kg had mean plasma concentrations of about 45 mcg/mL, whereas those over 150 kg had a mean level of less than 10 mcg/mL. Meanwhile, saturations appeared to escalate with concentration per patient-kilogram in a linear fashion from a mean of 85%-95%. "When you look at 95%-plus saturators, you see stratification into this real high-concentration and low-weight group," Dr. Foley said at the annual meeting of the American Academy of Neurology.

The findings led him to theorize that thinner patients are more at risk for PML because the higher saturations they develop block not only myelin-destroying lymphocytes from entering the central nervous system, as intended, but also lymphocytes that fight the JC virus, the cause of PML in those who carry it.

"We think there’s a link between serum concentration and saturation of lymphocytes in general, and that excessive saturation leads to near-complete stoppage of [lymphocyte] trafficking from blood vessels into brain parenchyma." Perhaps "we reach a threshold where we not only impede the cells that are programmed to cause MS, but also the trafficking of the cells that are programmed to kill viruses. We need to figure out what the optimal balance is," he said in an interview.

For now, "how we are approaching this is [by] dose-extending high-risk, JC virus antibody–positive populations out to 5-6 weeks, instead of dosing every 4 weeks," as the natalizumab label indicates. It "reduces concentrations in the last few weeks, and saturations decline. It may well be a viable approach for PML risk reduction," Dr. Foley said.

At the Rocky Mountain clinic, 14 patients who took natalizumab every 6 weeks had mean concentrations of 18.7 mcg/mL and saturations of 83.5%, whereas a group of about 160 patients on a 4-week dosing schedule had mean concentrations of 33.6 mcg/mL and saturations of 89.3%.

"You really want to avoid these high-concentration, high-saturation environments," he said.

The work was funded by the maker of natalizumab, Biogen Idec, and its distributor, Elan Pharmaceuticals. Dr. Foley is a scientific adviser to and a speaker for Biogen.

aotto@frontlinemedcom.com

SAN DIEGO – Thinner multiple sclerosis patients may be at higher risk for natalizumab-induced progressive multifocal leukoencephalopathy, according to researchers from the Rocky Mountain Multiple Sclerosis Research Group in Salt Lake City.

The risk may derive from the drug’s higher mean plasma concentrations and the greater saturation of lymphocyte receptors in such patients, lead investigator Dr. John Foley suggested.

He and his team reviewed 38 natalizumab (Tysabri)-induced progressive multifocal leukoencephalopathy (PML) cases – 11.5% of the current global total – and found that 24 of the patients were 70 kg or less and 29 were 80 kg or less. The median weight of the PML patients was 64 kg, substantially lower than the weight of the average MS patient, at least at the Rocky Mountain clinic.

At 60 kg or less, "there is a striking elevation in PML cases. [The] incidence definitely trends towards patients with lower body weights," said Dr. Foley, founder of the clinic.

To further explore the issue, his team also analyzed clinical data from 301 of its own natalizumab patients, plus data from 826 patients in the Swedish Natalizumab Registry, 799 patients from phase III trials, and patients from other sources.

In doing so, they also found that patients weighing less than 75 kg tend to develop higher plasma concentrations of the monoclonal antibody over time and are more likely to saturate 95% or more of the lymphocyte receptors that natalizumab targets, exceeding the saturation goal of about 85%.

Patients who weighed no more than 70 kg had mean plasma concentrations of about 45 mcg/mL, whereas those over 150 kg had a mean level of less than 10 mcg/mL. Meanwhile, saturations appeared to escalate with concentration per patient-kilogram in a linear fashion from a mean of 85%-95%. "When you look at 95%-plus saturators, you see stratification into this real high-concentration and low-weight group," Dr. Foley said at the annual meeting of the American Academy of Neurology.

The findings led him to theorize that thinner patients are more at risk for PML because the higher saturations they develop block not only myelin-destroying lymphocytes from entering the central nervous system, as intended, but also lymphocytes that fight the JC virus, the cause of PML in those who carry it.

"We think there’s a link between serum concentration and saturation of lymphocytes in general, and that excessive saturation leads to near-complete stoppage of [lymphocyte] trafficking from blood vessels into brain parenchyma." Perhaps "we reach a threshold where we not only impede the cells that are programmed to cause MS, but also the trafficking of the cells that are programmed to kill viruses. We need to figure out what the optimal balance is," he said in an interview.

For now, "how we are approaching this is [by] dose-extending high-risk, JC virus antibody–positive populations out to 5-6 weeks, instead of dosing every 4 weeks," as the natalizumab label indicates. It "reduces concentrations in the last few weeks, and saturations decline. It may well be a viable approach for PML risk reduction," Dr. Foley said.

At the Rocky Mountain clinic, 14 patients who took natalizumab every 6 weeks had mean concentrations of 18.7 mcg/mL and saturations of 83.5%, whereas a group of about 160 patients on a 4-week dosing schedule had mean concentrations of 33.6 mcg/mL and saturations of 89.3%.

"You really want to avoid these high-concentration, high-saturation environments," he said.

The work was funded by the maker of natalizumab, Biogen Idec, and its distributor, Elan Pharmaceuticals. Dr. Foley is a scientific adviser to and a speaker for Biogen.

aotto@frontlinemedcom.com

SAN DIEGO – Thinner multiple sclerosis patients may be at higher risk for natalizumab-induced progressive multifocal leukoencephalopathy, according to researchers from the Rocky Mountain Multiple Sclerosis Research Group in Salt Lake City.

The risk may derive from the drug’s higher mean plasma concentrations and the greater saturation of lymphocyte receptors in such patients, lead investigator Dr. John Foley suggested.

He and his team reviewed 38 natalizumab (Tysabri)-induced progressive multifocal leukoencephalopathy (PML) cases – 11.5% of the current global total – and found that 24 of the patients were 70 kg or less and 29 were 80 kg or less. The median weight of the PML patients was 64 kg, substantially lower than the weight of the average MS patient, at least at the Rocky Mountain clinic.

At 60 kg or less, "there is a striking elevation in PML cases. [The] incidence definitely trends towards patients with lower body weights," said Dr. Foley, founder of the clinic.

To further explore the issue, his team also analyzed clinical data from 301 of its own natalizumab patients, plus data from 826 patients in the Swedish Natalizumab Registry, 799 patients from phase III trials, and patients from other sources.

In doing so, they also found that patients weighing less than 75 kg tend to develop higher plasma concentrations of the monoclonal antibody over time and are more likely to saturate 95% or more of the lymphocyte receptors that natalizumab targets, exceeding the saturation goal of about 85%.

Patients who weighed no more than 70 kg had mean plasma concentrations of about 45 mcg/mL, whereas those over 150 kg had a mean level of less than 10 mcg/mL. Meanwhile, saturations appeared to escalate with concentration per patient-kilogram in a linear fashion from a mean of 85%-95%. "When you look at 95%-plus saturators, you see stratification into this real high-concentration and low-weight group," Dr. Foley said at the annual meeting of the American Academy of Neurology.

The findings led him to theorize that thinner patients are more at risk for PML because the higher saturations they develop block not only myelin-destroying lymphocytes from entering the central nervous system, as intended, but also lymphocytes that fight the JC virus, the cause of PML in those who carry it.

"We think there’s a link between serum concentration and saturation of lymphocytes in general, and that excessive saturation leads to near-complete stoppage of [lymphocyte] trafficking from blood vessels into brain parenchyma." Perhaps "we reach a threshold where we not only impede the cells that are programmed to cause MS, but also the trafficking of the cells that are programmed to kill viruses. We need to figure out what the optimal balance is," he said in an interview.

For now, "how we are approaching this is [by] dose-extending high-risk, JC virus antibody–positive populations out to 5-6 weeks, instead of dosing every 4 weeks," as the natalizumab label indicates. It "reduces concentrations in the last few weeks, and saturations decline. It may well be a viable approach for PML risk reduction," Dr. Foley said.

At the Rocky Mountain clinic, 14 patients who took natalizumab every 6 weeks had mean concentrations of 18.7 mcg/mL and saturations of 83.5%, whereas a group of about 160 patients on a 4-week dosing schedule had mean concentrations of 33.6 mcg/mL and saturations of 89.3%.

"You really want to avoid these high-concentration, high-saturation environments," he said.

The work was funded by the maker of natalizumab, Biogen Idec, and its distributor, Elan Pharmaceuticals. Dr. Foley is a scientific adviser to and a speaker for Biogen.

aotto@frontlinemedcom.com

SAN DIEGO – Most neurologists are aware of recent Food and Drug Administration safety warnings regarding the use of antiepileptic medications, but about 20% do not recognize these risks, results from a large membership survey demonstrated.

"FDA drug safety warnings are not systematically delivered to neurologists," Dr. Susan Shaw said at the annual meeting of the American Academy of Neurology. "The sources of information are numerous and varied. We also feel that the FDA drug safety warnings are not effectively delivered to neurologists."

Courtesy Dr. Susan Shaw

She based her remarks on an Internet-based survey distributed to 4,627 AAN members in 2012. Although the FDA issues drug safety communications and MedWatch alert e-mails, "these are only sent to those who are registered to receive the notifications," explained Dr. Shaw, a neurologist who is director of the epilepsy service line at Rancho Los Amigos National Rehabilitation Center, Downey, Calif., and is with the department of neurology at the University of Southern California, Los Angeles. The FDA may send alerts to physician specialty organizations such as the AAN, "which may then transmit the information to their members, but not all neurologists are members of the AAN," she noted. "The FDA may require drug manufacturers to update product inserts or highlight severe actions with ‘black box’ warnings or ‘dear health care provider’ letters. Still other neurologists rely on published articles or continuing medical education. Therefore, it is unknown whether the FDA’s alerts are effectively reaching neurologists."

Dr. Shaw and her associates set out to determine whether neurologists are aware of four recent FDA warnings regarding antiepileptic drugs (AEDs) and to determine whether neurologists are implementing recommended screening. Safety alert No. 1 was issued by the FDA on Dec. 12, 2007, and recommended screening for HLA-B*1502 in patients of Asian descent prior to treatment with carbamazepine, because of the risk of Stevens-Johnson syndrome and toxic epidermal necrolysis. "The risk of this haplotype is up to 10 times higher in some Asian countries than in countries with mostly Caucasian populations," Dr. Shaw said.

Safety alert No. 2 was the FDA announcement on Dec. 16, 2008, that required makers of AEDs to add labeling information warning that their use increases the risk of suicidal thoughts and behaviors. Safety alert No. 3 was the FDA healthcare provider notice released on Dec. 3, 2009, which recommended counseling for women of childbearing age who are taking valproate and labeling change for the drug because of the risk of congenital malformations in offspring of women treated with the drug during pregnancy. Safety alert No. 4 was the FDA drug safety communication and labeling change released on June 30, 2011, regarding the risk of impaired cognitive development in children exposed to valproate in utero.

"We do know that some of the FDA warnings, especially regarding suicidality, are controversial, but we think that it is important for providers to be aware of warnings and recommendations made by the FDA," Dr. Shaw said.

Of the 4,627 neurologists queried, 605 (13%) responded, which Dr. Shaw noted is a typical response rate for these types of surveys. The researchers excluded 100 who did not care for patients with epilepsy, which left a final survey sample size of 505 respondents from all 50 states and the District of Columbia. Their average age was 49 years and they had been in practice for an average of 22 years. The majority (96%) were board-certified in neurology, 40% worked in an academic hospital clinic, 32% worked in group practice, 18% worked in solo practice, and the remainder worked in other settings.

For each of the four safety alerts, "we asked questions to see if respondents had a general awareness of this risk," Dr. Shaw said. "We also asked questions to see if they knew more specific details regarding the risk."

Overall, about 80% of respondents did know about the four FDA safety alerts. "However, that does mean that approximately one-fifth of neurologists are not aware at all of the safety risks for these drugs," Dr. Shaw said. Knowledge of the specific details for each safety alert varied widely, from 34% to 74%.

The researchers also found that 29% of respondents had initiated carbamazepine in patients of Asian descent, but only 23% conducted the recommended haplotype testing for these patients. Most providers (93%) counseled women regarding birth defect risks while taking valproate, but only 34% could identify the specific risk of congenital malformations. Similarly, only 49% knew the degree to which scores on the Differential Ability Scale declined with in utero valproate exposure, compared with other AED monotherapy. In fact, 31% incorrectly believed that cognitive and developmental risks have not been established in offspring exposed to divalproex in utero.

The sources of drug safety alerts used by the respondents "were numerous, and there was no one universal source, which suggests that the safety information delivery is not done so systematically," Dr. Shaw said. The only characteristic of survey respondents associated with better knowledge of AED safety alerts was treating more epilepsy patients per year.

"We feel that a better system of doing risk notification may be warranted," she concluded. "In fact, when we asked the survey respondents, less than 5% of them wanted to continue the current system the way it is."

Most survey respondents preferred implementing a formal warning process via specialty organizations or e-mails of product insert warnings.

Dr. Shaw said that she had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

SAN DIEGO – Most neurologists are aware of recent Food and Drug Administration safety warnings regarding the use of antiepileptic medications, but about 20% do not recognize these risks, results from a large membership survey demonstrated.

"FDA drug safety warnings are not systematically delivered to neurologists," Dr. Susan Shaw said at the annual meeting of the American Academy of Neurology. "The sources of information are numerous and varied. We also feel that the FDA drug safety warnings are not effectively delivered to neurologists."

Courtesy Dr. Susan Shaw

She based her remarks on an Internet-based survey distributed to 4,627 AAN members in 2012. Although the FDA issues drug safety communications and MedWatch alert e-mails, "these are only sent to those who are registered to receive the notifications," explained Dr. Shaw, a neurologist who is director of the epilepsy service line at Rancho Los Amigos National Rehabilitation Center, Downey, Calif., and is with the department of neurology at the University of Southern California, Los Angeles. The FDA may send alerts to physician specialty organizations such as the AAN, "which may then transmit the information to their members, but not all neurologists are members of the AAN," she noted. "The FDA may require drug manufacturers to update product inserts or highlight severe actions with ‘black box’ warnings or ‘dear health care provider’ letters. Still other neurologists rely on published articles or continuing medical education. Therefore, it is unknown whether the FDA’s alerts are effectively reaching neurologists."

Dr. Shaw and her associates set out to determine whether neurologists are aware of four recent FDA warnings regarding antiepileptic drugs (AEDs) and to determine whether neurologists are implementing recommended screening. Safety alert No. 1 was issued by the FDA on Dec. 12, 2007, and recommended screening for HLA-B*1502 in patients of Asian descent prior to treatment with carbamazepine, because of the risk of Stevens-Johnson syndrome and toxic epidermal necrolysis. "The risk of this haplotype is up to 10 times higher in some Asian countries than in countries with mostly Caucasian populations," Dr. Shaw said.

Safety alert No. 2 was the FDA announcement on Dec. 16, 2008, that required makers of AEDs to add labeling information warning that their use increases the risk of suicidal thoughts and behaviors. Safety alert No. 3 was the FDA healthcare provider notice released on Dec. 3, 2009, which recommended counseling for women of childbearing age who are taking valproate and labeling change for the drug because of the risk of congenital malformations in offspring of women treated with the drug during pregnancy. Safety alert No. 4 was the FDA drug safety communication and labeling change released on June 30, 2011, regarding the risk of impaired cognitive development in children exposed to valproate in utero.

"We do know that some of the FDA warnings, especially regarding suicidality, are controversial, but we think that it is important for providers to be aware of warnings and recommendations made by the FDA," Dr. Shaw said.

Of the 4,627 neurologists queried, 605 (13%) responded, which Dr. Shaw noted is a typical response rate for these types of surveys. The researchers excluded 100 who did not care for patients with epilepsy, which left a final survey sample size of 505 respondents from all 50 states and the District of Columbia. Their average age was 49 years and they had been in practice for an average of 22 years. The majority (96%) were board-certified in neurology, 40% worked in an academic hospital clinic, 32% worked in group practice, 18% worked in solo practice, and the remainder worked in other settings.

For each of the four safety alerts, "we asked questions to see if respondents had a general awareness of this risk," Dr. Shaw said. "We also asked questions to see if they knew more specific details regarding the risk."

Overall, about 80% of respondents did know about the four FDA safety alerts. "However, that does mean that approximately one-fifth of neurologists are not aware at all of the safety risks for these drugs," Dr. Shaw said. Knowledge of the specific details for each safety alert varied widely, from 34% to 74%.

The researchers also found that 29% of respondents had initiated carbamazepine in patients of Asian descent, but only 23% conducted the recommended haplotype testing for these patients. Most providers (93%) counseled women regarding birth defect risks while taking valproate, but only 34% could identify the specific risk of congenital malformations. Similarly, only 49% knew the degree to which scores on the Differential Ability Scale declined with in utero valproate exposure, compared with other AED monotherapy. In fact, 31% incorrectly believed that cognitive and developmental risks have not been established in offspring exposed to divalproex in utero.

The sources of drug safety alerts used by the respondents "were numerous, and there was no one universal source, which suggests that the safety information delivery is not done so systematically," Dr. Shaw said. The only characteristic of survey respondents associated with better knowledge of AED safety alerts was treating more epilepsy patients per year.

"We feel that a better system of doing risk notification may be warranted," she concluded. "In fact, when we asked the survey respondents, less than 5% of them wanted to continue the current system the way it is."

Most survey respondents preferred implementing a formal warning process via specialty organizations or e-mails of product insert warnings.

Dr. Shaw said that she had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

SAN DIEGO – Most neurologists are aware of recent Food and Drug Administration safety warnings regarding the use of antiepileptic medications, but about 20% do not recognize these risks, results from a large membership survey demonstrated.

"FDA drug safety warnings are not systematically delivered to neurologists," Dr. Susan Shaw said at the annual meeting of the American Academy of Neurology. "The sources of information are numerous and varied. We also feel that the FDA drug safety warnings are not effectively delivered to neurologists."

Courtesy Dr. Susan Shaw

She based her remarks on an Internet-based survey distributed to 4,627 AAN members in 2012. Although the FDA issues drug safety communications and MedWatch alert e-mails, "these are only sent to those who are registered to receive the notifications," explained Dr. Shaw, a neurologist who is director of the epilepsy service line at Rancho Los Amigos National Rehabilitation Center, Downey, Calif., and is with the department of neurology at the University of Southern California, Los Angeles. The FDA may send alerts to physician specialty organizations such as the AAN, "which may then transmit the information to their members, but not all neurologists are members of the AAN," she noted. "The FDA may require drug manufacturers to update product inserts or highlight severe actions with ‘black box’ warnings or ‘dear health care provider’ letters. Still other neurologists rely on published articles or continuing medical education. Therefore, it is unknown whether the FDA’s alerts are effectively reaching neurologists."

Dr. Shaw and her associates set out to determine whether neurologists are aware of four recent FDA warnings regarding antiepileptic drugs (AEDs) and to determine whether neurologists are implementing recommended screening. Safety alert No. 1 was issued by the FDA on Dec. 12, 2007, and recommended screening for HLA-B*1502 in patients of Asian descent prior to treatment with carbamazepine, because of the risk of Stevens-Johnson syndrome and toxic epidermal necrolysis. "The risk of this haplotype is up to 10 times higher in some Asian countries than in countries with mostly Caucasian populations," Dr. Shaw said.

Safety alert No. 2 was the FDA announcement on Dec. 16, 2008, that required makers of AEDs to add labeling information warning that their use increases the risk of suicidal thoughts and behaviors. Safety alert No. 3 was the FDA healthcare provider notice released on Dec. 3, 2009, which recommended counseling for women of childbearing age who are taking valproate and labeling change for the drug because of the risk of congenital malformations in offspring of women treated with the drug during pregnancy. Safety alert No. 4 was the FDA drug safety communication and labeling change released on June 30, 2011, regarding the risk of impaired cognitive development in children exposed to valproate in utero.

"We do know that some of the FDA warnings, especially regarding suicidality, are controversial, but we think that it is important for providers to be aware of warnings and recommendations made by the FDA," Dr. Shaw said.

Of the 4,627 neurologists queried, 605 (13%) responded, which Dr. Shaw noted is a typical response rate for these types of surveys. The researchers excluded 100 who did not care for patients with epilepsy, which left a final survey sample size of 505 respondents from all 50 states and the District of Columbia. Their average age was 49 years and they had been in practice for an average of 22 years. The majority (96%) were board-certified in neurology, 40% worked in an academic hospital clinic, 32% worked in group practice, 18% worked in solo practice, and the remainder worked in other settings.

For each of the four safety alerts, "we asked questions to see if respondents had a general awareness of this risk," Dr. Shaw said. "We also asked questions to see if they knew more specific details regarding the risk."

Overall, about 80% of respondents did know about the four FDA safety alerts. "However, that does mean that approximately one-fifth of neurologists are not aware at all of the safety risks for these drugs," Dr. Shaw said. Knowledge of the specific details for each safety alert varied widely, from 34% to 74%.

The researchers also found that 29% of respondents had initiated carbamazepine in patients of Asian descent, but only 23% conducted the recommended haplotype testing for these patients. Most providers (93%) counseled women regarding birth defect risks while taking valproate, but only 34% could identify the specific risk of congenital malformations. Similarly, only 49% knew the degree to which scores on the Differential Ability Scale declined with in utero valproate exposure, compared with other AED monotherapy. In fact, 31% incorrectly believed that cognitive and developmental risks have not been established in offspring exposed to divalproex in utero.

The sources of drug safety alerts used by the respondents "were numerous, and there was no one universal source, which suggests that the safety information delivery is not done so systematically," Dr. Shaw said. The only characteristic of survey respondents associated with better knowledge of AED safety alerts was treating more epilepsy patients per year.

"We feel that a better system of doing risk notification may be warranted," she concluded. "In fact, when we asked the survey respondents, less than 5% of them wanted to continue the current system the way it is."

Most survey respondents preferred implementing a formal warning process via specialty organizations or e-mails of product insert warnings.

Dr. Shaw said that she had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

SAN DIEGO – Men and women with mild to moderate dementia who participated in a small pilot study involving a novel exercise program focused on movements required to maintain functions of daily living experienced improvements in cognitive function, physical performance, and caregiver burden, compared with those who did not participate.

"Currently available medications do no stop or slow progression of Alzheimer’s disease," Deborah E. Barnes, Ph.D., said at the annual meeting of the American Academy of Neurology. "They are associated with small improvements in cognitive function, but they have minimal impact on physical function, quality of life, and caregiver burden."

Doug Brunk/IMNG Medical Media

Speaking in hypothetical terms, Dr. Barnes continued, "What if we had an overlooked drug that was clinically proven in randomized, controlled trials to increase cognitive function and hippocampal volume in older adults, slow cognitive decline in individuals with mild cognitive impairment, enhance neurogenesis and reduce beta-amyloid in animal models? That would be pretty amazing. What if this drug also had other health benefits throughout the body and had minimal side effects?"

This candidate "drug," she proposed, is a program known as Preventing Loss of Independence Through Exercise (PLIÉ), which was developed by Dr. Barnes and her associates at the Osher Center for Integrative Medicine at the University of California, San Francisco (UCSF). The program combines elements of Eastern and Western exercise traditions and focuses on performing basic functional movements, increasing body awareness, and encouraging social engagement. "We met with experts in yoga, tai chi, Feldenkrais, physical therapy, occupational therapy, and mindfulness, and dance movement therapy and had them talk about what they felt worked the best in people with dementia, and we tried to pull out the commonalities across the different traditions," she explained.

In a pilot trial, the researchers studied 11 adults with mild to moderate dementia who attended an adult day care program in San Francisco. They were assigned to either the PLIÉ intervention group, which met 2-3 days per week for 18 weeks, or to a usual care group. Blinded assessors administered a battery of tests pre- and postintervention to study participants and their caregivers. Measures used for participants included the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog) to measure cognitive function, the Quality of Life in Alzheimer’s Disease (QoL-AD) tool to measure quality of life, and the Short Physical Performance Battery (SPPB) to measure physical function. Measures used for caregivers included the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory (ADCS-ADL) to measure participant function, the QoL-AD to measure participant quality of life, the Neuropsychiatric Inventory Questionnaire to measure the frequency and severity of dementia-related symptoms (NPI-FS), as well as the NPI Caregiver Distress Scale(NPI-D). The researchers also administered the Caregiver Burden Inventory (CBI).

Of the 11 study participants, 6 were assigned to the intervention group and 5 to usual care. The average age of participants was 84 years, and most (82%) were female. The mean age of caregivers was 56 years. The majority (82%) were daughters who had been caring for their parent for 3-4 years.

After 18 weeks, the intervention group had a decline of 4.6 points on the ADAS-cog (with lower scores being better) while the usual care group had an increase of 2.4 points on the measure, for an effect size of 0.76. "This is a substantially higher treatment effect than what’s usually seen with dementia medications, which is usually around the order of 0.20," noted Dr. Barnes of the department of psychiatry at UCSF. In addition, scores on the QoL-AD improved 6 points in the intervention group and 2.6 points in the usual care group, for an effect size of 0.83. Scores on the SPPB improved 1 point in the intervention group and 0.2 points in the usual care group, for an effect size of 0.34. "Although these effect sizes were not statistically significant because of the small sample size, they were well within the clinically meaningful range," she said.

There were no real differences for caregiver test measurements on participant function as measured by the ADCS-ADL scale, but caregiver-reported participant quality of life as measured by the QoL-AD improved 2.2 points in the intervention group, compared with 0 points in the usual care group, for an effect size of 0.33. For frequency and severity of the dementia-related symptoms on the NPI-FS, the intervention group declined 3.4 points, compared with 3 points for the usual care group, for an effect size of 0.02. Caregiver distress as measured by the NPI-D improved in the intervention group with a decline of 2.3 points, compared with an increase of 0.5 points in the usual care group, for an effect size of 0.28. There was an effect size of 0.49 for the PLIÉ intervention on the CBI, based on a decline of 5.5 points in the exercise group and an increase of 1.7 points in the usual care group.

Dr. Barnes speculated that the PLIÉ program is effective in part "because there are repetitions of the same sequence of events in each class. We know that memory for events is impaired in people with dementia, but procedural memory is actually maintained pretty well. What we found in the class was that people would come in after they’d been doing it a few weeks. They would not remember having been in the class before, but we would start going through the movements, and they knew exactly what do to. They knew which movement came next in the sequence, so they were building procedural memory for these movements."

Another unique feature of the program, she said, is that it incorporates simple functional movements that increase in complexity as participants become "more facile with the movements, really focusing on being able to stand and sit down safely – basic physical functions that decline in dementia. We also have a slow pace, which gives them enough time to absorb the information and consolidate it."

Dr. Barnes also noted that social connection developed between the study participants over time. "During rests between movements, people in the program often shared personal stories," she said. "The movements themselves also encouraged group interaction by having participants reach out to shake hands, for example. These enhanced social connections may have contributed to improvements in quality of life."

The study was funded by a gift to the Osher Center for Integrative Medicine at the University of California, San Francisco. Dr. Barnes said she had no relevant financial disclosures.

dbrunk@frontlinemedcom.com

SAN DIEGO – Men and women with mild to moderate dementia who participated in a small pilot study involving a novel exercise program focused on movements required to maintain functions of daily living experienced improvements in cognitive function, physical performance, and caregiver burden, compared with those who did not participate.

"Currently available medications do no stop or slow progression of Alzheimer’s disease," Deborah E. Barnes, Ph.D., said at the annual meeting of the American Academy of Neurology. "They are associated with small improvements in cognitive function, but they have minimal impact on physical function, quality of life, and caregiver burden."

Doug Brunk/IMNG Medical Media

Speaking in hypothetical terms, Dr. Barnes continued, "What if we had an overlooked drug that was clinically proven in randomized, controlled trials to increase cognitive function and hippocampal volume in older adults, slow cognitive decline in individuals with mild cognitive impairment, enhance neurogenesis and reduce beta-amyloid in animal models? That would be pretty amazing. What if this drug also had other health benefits throughout the body and had minimal side effects?"

This candidate "drug," she proposed, is a program known as Preventing Loss of Independence Through Exercise (PLIÉ), which was developed by Dr. Barnes and her associates at the Osher Center for Integrative Medicine at the University of California, San Francisco (UCSF). The program combines elements of Eastern and Western exercise traditions and focuses on performing basic functional movements, increasing body awareness, and encouraging social engagement. "We met with experts in yoga, tai chi, Feldenkrais, physical therapy, occupational therapy, and mindfulness, and dance movement therapy and had them talk about what they felt worked the best in people with dementia, and we tried to pull out the commonalities across the different traditions," she explained.

In a pilot trial, the researchers studied 11 adults with mild to moderate dementia who attended an adult day care program in San Francisco. They were assigned to either the PLIÉ intervention group, which met 2-3 days per week for 18 weeks, or to a usual care group. Blinded assessors administered a battery of tests pre- and postintervention to study participants and their caregivers. Measures used for participants included the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog) to measure cognitive function, the Quality of Life in Alzheimer’s Disease (QoL-AD) tool to measure quality of life, and the Short Physical Performance Battery (SPPB) to measure physical function. Measures used for caregivers included the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory (ADCS-ADL) to measure participant function, the QoL-AD to measure participant quality of life, the Neuropsychiatric Inventory Questionnaire to measure the frequency and severity of dementia-related symptoms (NPI-FS), as well as the NPI Caregiver Distress Scale(NPI-D). The researchers also administered the Caregiver Burden Inventory (CBI).

Of the 11 study participants, 6 were assigned to the intervention group and 5 to usual care. The average age of participants was 84 years, and most (82%) were female. The mean age of caregivers was 56 years. The majority (82%) were daughters who had been caring for their parent for 3-4 years.

After 18 weeks, the intervention group had a decline of 4.6 points on the ADAS-cog (with lower scores being better) while the usual care group had an increase of 2.4 points on the measure, for an effect size of 0.76. "This is a substantially higher treatment effect than what’s usually seen with dementia medications, which is usually around the order of 0.20," noted Dr. Barnes of the department of psychiatry at UCSF. In addition, scores on the QoL-AD improved 6 points in the intervention group and 2.6 points in the usual care group, for an effect size of 0.83. Scores on the SPPB improved 1 point in the intervention group and 0.2 points in the usual care group, for an effect size of 0.34. "Although these effect sizes were not statistically significant because of the small sample size, they were well within the clinically meaningful range," she said.

There were no real differences for caregiver test measurements on participant function as measured by the ADCS-ADL scale, but caregiver-reported participant quality of life as measured by the QoL-AD improved 2.2 points in the intervention group, compared with 0 points in the usual care group, for an effect size of 0.33. For frequency and severity of the dementia-related symptoms on the NPI-FS, the intervention group declined 3.4 points, compared with 3 points for the usual care group, for an effect size of 0.02. Caregiver distress as measured by the NPI-D improved in the intervention group with a decline of 2.3 points, compared with an increase of 0.5 points in the usual care group, for an effect size of 0.28. There was an effect size of 0.49 for the PLIÉ intervention on the CBI, based on a decline of 5.5 points in the exercise group and an increase of 1.7 points in the usual care group.

Dr. Barnes speculated that the PLIÉ program is effective in part "because there are repetitions of the same sequence of events in each class. We know that memory for events is impaired in people with dementia, but procedural memory is actually maintained pretty well. What we found in the class was that people would come in after they’d been doing it a few weeks. They would not remember having been in the class before, but we would start going through the movements, and they knew exactly what do to. They knew which movement came next in the sequence, so they were building procedural memory for these movements."

Another unique feature of the program, she said, is that it incorporates simple functional movements that increase in complexity as participants become "more facile with the movements, really focusing on being able to stand and sit down safely – basic physical functions that decline in dementia. We also have a slow pace, which gives them enough time to absorb the information and consolidate it."

Dr. Barnes also noted that social connection developed between the study participants over time. "During rests between movements, people in the program often shared personal stories," she said. "The movements themselves also encouraged group interaction by having participants reach out to shake hands, for example. These enhanced social connections may have contributed to improvements in quality of life."

The study was funded by a gift to the Osher Center for Integrative Medicine at the University of California, San Francisco. Dr. Barnes said she had no relevant financial disclosures.

dbrunk@frontlinemedcom.com

SAN DIEGO – Men and women with mild to moderate dementia who participated in a small pilot study involving a novel exercise program focused on movements required to maintain functions of daily living experienced improvements in cognitive function, physical performance, and caregiver burden, compared with those who did not participate.

"Currently available medications do no stop or slow progression of Alzheimer’s disease," Deborah E. Barnes, Ph.D., said at the annual meeting of the American Academy of Neurology. "They are associated with small improvements in cognitive function, but they have minimal impact on physical function, quality of life, and caregiver burden."

Doug Brunk/IMNG Medical Media

Speaking in hypothetical terms, Dr. Barnes continued, "What if we had an overlooked drug that was clinically proven in randomized, controlled trials to increase cognitive function and hippocampal volume in older adults, slow cognitive decline in individuals with mild cognitive impairment, enhance neurogenesis and reduce beta-amyloid in animal models? That would be pretty amazing. What if this drug also had other health benefits throughout the body and had minimal side effects?"

This candidate "drug," she proposed, is a program known as Preventing Loss of Independence Through Exercise (PLIÉ), which was developed by Dr. Barnes and her associates at the Osher Center for Integrative Medicine at the University of California, San Francisco (UCSF). The program combines elements of Eastern and Western exercise traditions and focuses on performing basic functional movements, increasing body awareness, and encouraging social engagement. "We met with experts in yoga, tai chi, Feldenkrais, physical therapy, occupational therapy, and mindfulness, and dance movement therapy and had them talk about what they felt worked the best in people with dementia, and we tried to pull out the commonalities across the different traditions," she explained.

In a pilot trial, the researchers studied 11 adults with mild to moderate dementia who attended an adult day care program in San Francisco. They were assigned to either the PLIÉ intervention group, which met 2-3 days per week for 18 weeks, or to a usual care group. Blinded assessors administered a battery of tests pre- and postintervention to study participants and their caregivers. Measures used for participants included the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog) to measure cognitive function, the Quality of Life in Alzheimer’s Disease (QoL-AD) tool to measure quality of life, and the Short Physical Performance Battery (SPPB) to measure physical function. Measures used for caregivers included the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory (ADCS-ADL) to measure participant function, the QoL-AD to measure participant quality of life, the Neuropsychiatric Inventory Questionnaire to measure the frequency and severity of dementia-related symptoms (NPI-FS), as well as the NPI Caregiver Distress Scale(NPI-D). The researchers also administered the Caregiver Burden Inventory (CBI).

Of the 11 study participants, 6 were assigned to the intervention group and 5 to usual care. The average age of participants was 84 years, and most (82%) were female. The mean age of caregivers was 56 years. The majority (82%) were daughters who had been caring for their parent for 3-4 years.

After 18 weeks, the intervention group had a decline of 4.6 points on the ADAS-cog (with lower scores being better) while the usual care group had an increase of 2.4 points on the measure, for an effect size of 0.76. "This is a substantially higher treatment effect than what’s usually seen with dementia medications, which is usually around the order of 0.20," noted Dr. Barnes of the department of psychiatry at UCSF. In addition, scores on the QoL-AD improved 6 points in the intervention group and 2.6 points in the usual care group, for an effect size of 0.83. Scores on the SPPB improved 1 point in the intervention group and 0.2 points in the usual care group, for an effect size of 0.34. "Although these effect sizes were not statistically significant because of the small sample size, they were well within the clinically meaningful range," she said.

There were no real differences for caregiver test measurements on participant function as measured by the ADCS-ADL scale, but caregiver-reported participant quality of life as measured by the QoL-AD improved 2.2 points in the intervention group, compared with 0 points in the usual care group, for an effect size of 0.33. For frequency and severity of the dementia-related symptoms on the NPI-FS, the intervention group declined 3.4 points, compared with 3 points for the usual care group, for an effect size of 0.02. Caregiver distress as measured by the NPI-D improved in the intervention group with a decline of 2.3 points, compared with an increase of 0.5 points in the usual care group, for an effect size of 0.28. There was an effect size of 0.49 for the PLIÉ intervention on the CBI, based on a decline of 5.5 points in the exercise group and an increase of 1.7 points in the usual care group.

Dr. Barnes speculated that the PLIÉ program is effective in part "because there are repetitions of the same sequence of events in each class. We know that memory for events is impaired in people with dementia, but procedural memory is actually maintained pretty well. What we found in the class was that people would come in after they’d been doing it a few weeks. They would not remember having been in the class before, but we would start going through the movements, and they knew exactly what do to. They knew which movement came next in the sequence, so they were building procedural memory for these movements."

Another unique feature of the program, she said, is that it incorporates simple functional movements that increase in complexity as participants become "more facile with the movements, really focusing on being able to stand and sit down safely – basic physical functions that decline in dementia. We also have a slow pace, which gives them enough time to absorb the information and consolidate it."

Dr. Barnes also noted that social connection developed between the study participants over time. "During rests between movements, people in the program often shared personal stories," she said. "The movements themselves also encouraged group interaction by having participants reach out to shake hands, for example. These enhanced social connections may have contributed to improvements in quality of life."

The study was funded by a gift to the Osher Center for Integrative Medicine at the University of California, San Francisco. Dr. Barnes said she had no relevant financial disclosures.

dbrunk@frontlinemedcom.com

SAN DIEGO – The use of pillboxes and other medication management aids by patients with Parkinson’s disease was not associated with increased adherence, results from a single-center study showed.

In fact, those who relied on cell phone alarms actually had worse adherence to their medication. "Medication adherence aids – particularly phone alarms – do not magically improve adherence to medication regimens," Dr. Melissa Armstrong said in an interview after the annual meeting of the American Academy of Neurology, where the study was presented during a poster session.

"I still encourage my patients to use various aids, especially since we don’t have anything better, but I caution them that they shouldn’t think these aids are going to miraculously help them remember to take their doses. It’s still going to take commitment and work. I particularly caution my younger Parkinson’s disease patients using phone alarms that they need to choose good ringtones, be attentive to the reminders, and be careful not to just switch off the phone alarm and proceed on with their day without taking their medications."

In a study conducted at the University of Maryland Parkinson’s disease and movement disorders center in Baltimore, Dr. Armstrong and her associates set out to determine how commonly Parkinson’s patients use medication management aids and to evaluate whether the use of such aids is associated with improved adherence.

"There is little work on this in Parkinson’s disease, despite the complex medication regimens that people with Parkinson’s disease have," said Dr. Armstrong of the department of neurology at the university. "Also, from a clinical perspective, physicians at our movement disorders center realized that we didn’t know how many of our patients were already using different aids to help them remember to take their medications. We thus decided to investigate what our patients are already trying and whether or not the aids are helping."

Patients with Parkinson’s disease for at least 1 year and who were responsible for managing their own medications were eligible for the trial. Referring physicians completed the Unified Parkinsons Disease Rating Scale, and study participants completed the Montreal Cognitive Assessment (MoCA), a medication adherence aid questionnaire, and the 8-item Morisky Medication Adherence Scale (MMAS-8). The mean age of study participants was 69 years, 67% were male, and 93% were white. They were on an average of 2.4 Parkinson’s drugs and an average of 6.9 total drugs.

Of the 104 patients, 78% were adherent to their medications (score of 0-3 on the MMAS-8), and 77 (74%) reported use of one or more aids to manage their medications. These aids were chiefly pillboxes (used by 70 patients, 55 of whom met adherence criteria), followed by 10 who used a cell phone alarm, 7 who used a watch with an alarm, and 6 who used a pillbox with an alarm. Another 27 used no adherence aid.

Overall, Dr. Armstrong and her associates found that 52 (68%) of the 77 patients who used an adherence aid met adherence criteria, the use of adherence aids did not improve medication adherence from a statistical standpoint (P = .58), and the use of a cell phone alarm worsened adherence, with only 5 of 10 users meeting adherence criteria (P less than .05). "This could be because phones are easy to turn off without further response and because mobile phone sounds are so frequent they are not effective," Dr. Armstrong said in the poster. "Future research is needed to investigate the relationship between cell phone alarm use and adherence, especially as their use increases."

Dr. Armstrong acknowledged that the relatively small sample size is a limitation of the study. She said she had no relevant financial disclosures.

dbrunk@frontlinemedcom.com

SAN DIEGO – The use of pillboxes and other medication management aids by patients with Parkinson’s disease was not associated with increased adherence, results from a single-center study showed.

In fact, those who relied on cell phone alarms actually had worse adherence to their medication. "Medication adherence aids – particularly phone alarms – do not magically improve adherence to medication regimens," Dr. Melissa Armstrong said in an interview after the annual meeting of the American Academy of Neurology, where the study was presented during a poster session.

"I still encourage my patients to use various aids, especially since we don’t have anything better, but I caution them that they shouldn’t think these aids are going to miraculously help them remember to take their doses. It’s still going to take commitment and work. I particularly caution my younger Parkinson’s disease patients using phone alarms that they need to choose good ringtones, be attentive to the reminders, and be careful not to just switch off the phone alarm and proceed on with their day without taking their medications."

In a study conducted at the University of Maryland Parkinson’s disease and movement disorders center in Baltimore, Dr. Armstrong and her associates set out to determine how commonly Parkinson’s patients use medication management aids and to evaluate whether the use of such aids is associated with improved adherence.

"There is little work on this in Parkinson’s disease, despite the complex medication regimens that people with Parkinson’s disease have," said Dr. Armstrong of the department of neurology at the university. "Also, from a clinical perspective, physicians at our movement disorders center realized that we didn’t know how many of our patients were already using different aids to help them remember to take their medications. We thus decided to investigate what our patients are already trying and whether or not the aids are helping."

Patients with Parkinson’s disease for at least 1 year and who were responsible for managing their own medications were eligible for the trial. Referring physicians completed the Unified Parkinsons Disease Rating Scale, and study participants completed the Montreal Cognitive Assessment (MoCA), a medication adherence aid questionnaire, and the 8-item Morisky Medication Adherence Scale (MMAS-8). The mean age of study participants was 69 years, 67% were male, and 93% were white. They were on an average of 2.4 Parkinson’s drugs and an average of 6.9 total drugs.

Of the 104 patients, 78% were adherent to their medications (score of 0-3 on the MMAS-8), and 77 (74%) reported use of one or more aids to manage their medications. These aids were chiefly pillboxes (used by 70 patients, 55 of whom met adherence criteria), followed by 10 who used a cell phone alarm, 7 who used a watch with an alarm, and 6 who used a pillbox with an alarm. Another 27 used no adherence aid.

Overall, Dr. Armstrong and her associates found that 52 (68%) of the 77 patients who used an adherence aid met adherence criteria, the use of adherence aids did not improve medication adherence from a statistical standpoint (P = .58), and the use of a cell phone alarm worsened adherence, with only 5 of 10 users meeting adherence criteria (P less than .05). "This could be because phones are easy to turn off without further response and because mobile phone sounds are so frequent they are not effective," Dr. Armstrong said in the poster. "Future research is needed to investigate the relationship between cell phone alarm use and adherence, especially as their use increases."

Dr. Armstrong acknowledged that the relatively small sample size is a limitation of the study. She said she had no relevant financial disclosures.

dbrunk@frontlinemedcom.com

SAN DIEGO – The use of pillboxes and other medication management aids by patients with Parkinson’s disease was not associated with increased adherence, results from a single-center study showed.

In fact, those who relied on cell phone alarms actually had worse adherence to their medication. "Medication adherence aids – particularly phone alarms – do not magically improve adherence to medication regimens," Dr. Melissa Armstrong said in an interview after the annual meeting of the American Academy of Neurology, where the study was presented during a poster session.

"I still encourage my patients to use various aids, especially since we don’t have anything better, but I caution them that they shouldn’t think these aids are going to miraculously help them remember to take their doses. It’s still going to take commitment and work. I particularly caution my younger Parkinson’s disease patients using phone alarms that they need to choose good ringtones, be attentive to the reminders, and be careful not to just switch off the phone alarm and proceed on with their day without taking their medications."

In a study conducted at the University of Maryland Parkinson’s disease and movement disorders center in Baltimore, Dr. Armstrong and her associates set out to determine how commonly Parkinson’s patients use medication management aids and to evaluate whether the use of such aids is associated with improved adherence.

"There is little work on this in Parkinson’s disease, despite the complex medication regimens that people with Parkinson’s disease have," said Dr. Armstrong of the department of neurology at the university. "Also, from a clinical perspective, physicians at our movement disorders center realized that we didn’t know how many of our patients were already using different aids to help them remember to take their medications. We thus decided to investigate what our patients are already trying and whether or not the aids are helping."

Patients with Parkinson’s disease for at least 1 year and who were responsible for managing their own medications were eligible for the trial. Referring physicians completed the Unified Parkinsons Disease Rating Scale, and study participants completed the Montreal Cognitive Assessment (MoCA), a medication adherence aid questionnaire, and the 8-item Morisky Medication Adherence Scale (MMAS-8). The mean age of study participants was 69 years, 67% were male, and 93% were white. They were on an average of 2.4 Parkinson’s drugs and an average of 6.9 total drugs.

Of the 104 patients, 78% were adherent to their medications (score of 0-3 on the MMAS-8), and 77 (74%) reported use of one or more aids to manage their medications. These aids were chiefly pillboxes (used by 70 patients, 55 of whom met adherence criteria), followed by 10 who used a cell phone alarm, 7 who used a watch with an alarm, and 6 who used a pillbox with an alarm. Another 27 used no adherence aid.

Overall, Dr. Armstrong and her associates found that 52 (68%) of the 77 patients who used an adherence aid met adherence criteria, the use of adherence aids did not improve medication adherence from a statistical standpoint (P = .58), and the use of a cell phone alarm worsened adherence, with only 5 of 10 users meeting adherence criteria (P less than .05). "This could be because phones are easy to turn off without further response and because mobile phone sounds are so frequent they are not effective," Dr. Armstrong said in the poster. "Future research is needed to investigate the relationship between cell phone alarm use and adherence, especially as their use increases."

Dr. Armstrong acknowledged that the relatively small sample size is a limitation of the study. She said she had no relevant financial disclosures.

dbrunk@frontlinemedcom.com

SAN DIEGO – Robust behavioral changes are not common in presymptomatic familial Alzheimer’s disease, but increases in certain behaviors such as agitation, apathy, and appetitive changes can accompany early cognitive changes, results from a large ongoing study demonstrated.

The findings "are consistent with observations in late-onset Alzheimer’s disease and support behavioral changes in familial Alzheimer’s disease being a state associated with incipient Alzheimer’s pathology rather than a life-long disposition," Dr. John M. Ringman said at the annual meeting of the American Academy of Neurology.

"It’s well established now that the neuropathology of Alzheimer’s disease begins 15-20 years prior to overt symptoms," said Dr. Ringman, a neurologist at the Mary S. Easton Center for Alzheimer’s Disease Research at the University of California, Los Angeles. "Symptoms of depression, anxiety, apathy, and irritability are more frequent in persons with mild cognitive impairment (MCI). Further studies suggest that the presence of such symptoms in the context of MCI may better predict who will progress to develop Alzheimer’s disease."

Previous data published by Dr. Ringman and his associates suggest an increased degree of depressive symptoms in otherwise asymptomatic women inheriting PSEN1 mutations relative to their non–mutation carrying kin (J. Neurol. Neurosurg. Psychiatry 2004; 75:500-2). A study of persons destined to develop familial Alzheimer’s disease (FAD) "can help us differentiate between such symptoms as a ‘trait’ associated with a predisposition to AD or a ‘state’ related to the incipient development of AD pathology," he said.

At the meeting, Dr. Ringman presented findings from the first 212 men and women enrolled in the Dominantly Inherited Alzheimer Network (DIAN), an international multicenter study intended to characterize early clinical and biomarker changes occurring in people who inherit known FAD mutations in the PSEN1, APP, or PSEN2 genes. Men and woman at 50% risk for inheriting such a mutation underwent comprehensive evaluations including the Neuropsychiatric Inventory-Q (NPI-Q), the 15-item Geriatric Depression Scale (GDS), and the Clinical Dementia Rating Scale (CDR). Subjects who were aware of their mutation status were excluded from analysis.

The investigators classified FAD mutation carriers as being asymptomatic (defined as a CDR score of 0), mildly symptomatic (defined as a CDR score of 0.5), or overtly symptomatic (defined as a CDR score of greater than 0.5).* The researchers then compared FAD mutation carriers to noncarriers with respect to the frequency of behavioral changes on the NPI-Q and depression severity on the GDS. The 212 study participants included 133 mutation carriers and 79 noncarriers.

Of the 212 subjects, Dr. Ringman reported that 159 were at risk for PSEN1 mutations, 19 for PSEN2 mutations, and 34 for APP mutations. The 133 mutation carriers included 75 who were asymptomatic, 37 with mild symptoms, and 21 who were overtly affected. The researchers observed no statistically significant differences between asymptomatic mutation carriers and noncarriers in terms of neuropsychiatric symptoms. However, compared with noncarriers, mutation carriers with CDR scores of 0.5 demonstrated a significantly higher frequency of agitation (30% vs. 4%, respectively), apathy (41% vs. 3%), appetitive changes (30% vs. 9%), depressive symptoms (49% vs. 15%), disinhibition (16% vs. 1%), irritability (51% vs. 10%), and sleep changes (32% vs. 4%). In addition, the mean GDS score was mildly elevated in mildly symptomatic mutation carriers, compared with noncarriers (3.7 vs. 1.1; P value less than .001).

The study was funded by the National Institute on Aging, the Easton Consortium for Alzheimer’s Disease Drug Discovery and Biomarker Development, and UCLA’s Alzheimer’s Disease Research Center and Clinical Translational Research Institute. Dr. Ringman reported having no financial disclosures relevant to the study.

* 4/3/13, Correction to CDR score definitions.

dbrunk@frontlinemedcom.com

SAN DIEGO – Robust behavioral changes are not common in presymptomatic familial Alzheimer’s disease, but increases in certain behaviors such as agitation, apathy, and appetitive changes can accompany early cognitive changes, results from a large ongoing study demonstrated.

The findings "are consistent with observations in late-onset Alzheimer’s disease and support behavioral changes in familial Alzheimer’s disease being a state associated with incipient Alzheimer’s pathology rather than a life-long disposition," Dr. John M. Ringman said at the annual meeting of the American Academy of Neurology.

"It’s well established now that the neuropathology of Alzheimer’s disease begins 15-20 years prior to overt symptoms," said Dr. Ringman, a neurologist at the Mary S. Easton Center for Alzheimer’s Disease Research at the University of California, Los Angeles. "Symptoms of depression, anxiety, apathy, and irritability are more frequent in persons with mild cognitive impairment (MCI). Further studies suggest that the presence of such symptoms in the context of MCI may better predict who will progress to develop Alzheimer’s disease."

Previous data published by Dr. Ringman and his associates suggest an increased degree of depressive symptoms in otherwise asymptomatic women inheriting PSEN1 mutations relative to their non–mutation carrying kin (J. Neurol. Neurosurg. Psychiatry 2004; 75:500-2). A study of persons destined to develop familial Alzheimer’s disease (FAD) "can help us differentiate between such symptoms as a ‘trait’ associated with a predisposition to AD or a ‘state’ related to the incipient development of AD pathology," he said.

At the meeting, Dr. Ringman presented findings from the first 212 men and women enrolled in the Dominantly Inherited Alzheimer Network (DIAN), an international multicenter study intended to characterize early clinical and biomarker changes occurring in people who inherit known FAD mutations in the PSEN1, APP, or PSEN2 genes. Men and woman at 50% risk for inheriting such a mutation underwent comprehensive evaluations including the Neuropsychiatric Inventory-Q (NPI-Q), the 15-item Geriatric Depression Scale (GDS), and the Clinical Dementia Rating Scale (CDR). Subjects who were aware of their mutation status were excluded from analysis.

The investigators classified FAD mutation carriers as being asymptomatic (defined as a CDR score of 0), mildly symptomatic (defined as a CDR score of 0.5), or overtly symptomatic (defined as a CDR score of greater than 0.5).* The researchers then compared FAD mutation carriers to noncarriers with respect to the frequency of behavioral changes on the NPI-Q and depression severity on the GDS. The 212 study participants included 133 mutation carriers and 79 noncarriers.

Of the 212 subjects, Dr. Ringman reported that 159 were at risk for PSEN1 mutations, 19 for PSEN2 mutations, and 34 for APP mutations. The 133 mutation carriers included 75 who were asymptomatic, 37 with mild symptoms, and 21 who were overtly affected. The researchers observed no statistically significant differences between asymptomatic mutation carriers and noncarriers in terms of neuropsychiatric symptoms. However, compared with noncarriers, mutation carriers with CDR scores of 0.5 demonstrated a significantly higher frequency of agitation (30% vs. 4%, respectively), apathy (41% vs. 3%), appetitive changes (30% vs. 9%), depressive symptoms (49% vs. 15%), disinhibition (16% vs. 1%), irritability (51% vs. 10%), and sleep changes (32% vs. 4%). In addition, the mean GDS score was mildly elevated in mildly symptomatic mutation carriers, compared with noncarriers (3.7 vs. 1.1; P value less than .001).

The study was funded by the National Institute on Aging, the Easton Consortium for Alzheimer’s Disease Drug Discovery and Biomarker Development, and UCLA’s Alzheimer’s Disease Research Center and Clinical Translational Research Institute. Dr. Ringman reported having no financial disclosures relevant to the study.

* 4/3/13, Correction to CDR score definitions.

dbrunk@frontlinemedcom.com

SAN DIEGO – Robust behavioral changes are not common in presymptomatic familial Alzheimer’s disease, but increases in certain behaviors such as agitation, apathy, and appetitive changes can accompany early cognitive changes, results from a large ongoing study demonstrated.

The findings "are consistent with observations in late-onset Alzheimer’s disease and support behavioral changes in familial Alzheimer’s disease being a state associated with incipient Alzheimer’s pathology rather than a life-long disposition," Dr. John M. Ringman said at the annual meeting of the American Academy of Neurology.

"It’s well established now that the neuropathology of Alzheimer’s disease begins 15-20 years prior to overt symptoms," said Dr. Ringman, a neurologist at the Mary S. Easton Center for Alzheimer’s Disease Research at the University of California, Los Angeles. "Symptoms of depression, anxiety, apathy, and irritability are more frequent in persons with mild cognitive impairment (MCI). Further studies suggest that the presence of such symptoms in the context of MCI may better predict who will progress to develop Alzheimer’s disease."

Previous data published by Dr. Ringman and his associates suggest an increased degree of depressive symptoms in otherwise asymptomatic women inheriting PSEN1 mutations relative to their non–mutation carrying kin (J. Neurol. Neurosurg. Psychiatry 2004; 75:500-2). A study of persons destined to develop familial Alzheimer’s disease (FAD) "can help us differentiate between such symptoms as a ‘trait’ associated with a predisposition to AD or a ‘state’ related to the incipient development of AD pathology," he said.

At the meeting, Dr. Ringman presented findings from the first 212 men and women enrolled in the Dominantly Inherited Alzheimer Network (DIAN), an international multicenter study intended to characterize early clinical and biomarker changes occurring in people who inherit known FAD mutations in the PSEN1, APP, or PSEN2 genes. Men and woman at 50% risk for inheriting such a mutation underwent comprehensive evaluations including the Neuropsychiatric Inventory-Q (NPI-Q), the 15-item Geriatric Depression Scale (GDS), and the Clinical Dementia Rating Scale (CDR). Subjects who were aware of their mutation status were excluded from analysis.

The investigators classified FAD mutation carriers as being asymptomatic (defined as a CDR score of 0), mildly symptomatic (defined as a CDR score of 0.5), or overtly symptomatic (defined as a CDR score of greater than 0.5).* The researchers then compared FAD mutation carriers to noncarriers with respect to the frequency of behavioral changes on the NPI-Q and depression severity on the GDS. The 212 study participants included 133 mutation carriers and 79 noncarriers.

Of the 212 subjects, Dr. Ringman reported that 159 were at risk for PSEN1 mutations, 19 for PSEN2 mutations, and 34 for APP mutations. The 133 mutation carriers included 75 who were asymptomatic, 37 with mild symptoms, and 21 who were overtly affected. The researchers observed no statistically significant differences between asymptomatic mutation carriers and noncarriers in terms of neuropsychiatric symptoms. However, compared with noncarriers, mutation carriers with CDR scores of 0.5 demonstrated a significantly higher frequency of agitation (30% vs. 4%, respectively), apathy (41% vs. 3%), appetitive changes (30% vs. 9%), depressive symptoms (49% vs. 15%), disinhibition (16% vs. 1%), irritability (51% vs. 10%), and sleep changes (32% vs. 4%). In addition, the mean GDS score was mildly elevated in mildly symptomatic mutation carriers, compared with noncarriers (3.7 vs. 1.1; P value less than .001).

The study was funded by the National Institute on Aging, the Easton Consortium for Alzheimer’s Disease Drug Discovery and Biomarker Development, and UCLA’s Alzheimer’s Disease Research Center and Clinical Translational Research Institute. Dr. Ringman reported having no financial disclosures relevant to the study.

* 4/3/13, Correction to CDR score definitions.

dbrunk@frontlinemedcom.com

SAN DIEGO – Percutaneous transluminal venous angioplasty – also known as "liberation therapy" – doesn’t help people with multiple sclerosis and may increase MS brain activity in the short term, according to a small, randomized, sham-controlled trial from the State University of New York at Buffalo, the first randomized trial to investigate the procedure.

It "was ineffective in correcting" chronic cerebrospinal venous insufficiency (CCSVI), the recently described condition it targets. "The results ... caution against widespread adoption of venous angioplasty in the management of patients with MS outside of rigorous clinical trials," the investigators concluded.

The findings follow a recent Food and Drug Administration warning that PTVA (percutaneous transluminal venous angioplasty) can cause deaths and injuries, including strokes, damage to the treated vein, blood clots, cranial nerve damage, abdominal bleeding, and detachment and migration of stents.

The idea is to use balloon angioplasty and stents to widen veins in the chests and necks that appear to be narrowed in some MS patients. Proponents of the procedure say that those narrowed veins impair blood flow and lead to disease progression. The researchers who discovered the problem dubbed it CCSVI. A cottage industry has since sprung up to offer PTVA to MS patients.

The FDA noted in its warning that there have been no "controlled ... rigorously conducted, properly targeted" studies of the issue; that may have changed when Dr. Robert Zivadinov, a professor in the department of neurology at SUNY-Buffalo, presented his team’s findings at the annual meeting of the American Academy of Neurology.

"When you reopened those veins in the neck, I think something happened in reperfusing the brain and re-exacerbating disease activity. The message of this is clear. The majority of patients who are relapsing-remitting should not undergo this treatment," he said in an interview.

Ten patients got PTVA in the first phase of the study. The second phase randomized 9 to PTVA and 10 to a sham intervention. Most had relapsing-remitting MS.

There were no MS relapses in the first phase, but PTVA patients had more relapses (4 vs. 1; P = .389) and more MRI disease activity (cumulative number of new contrast-enhancing lesions (19 vs. 3; P = .062) and new T2 lesions (17 vs. 3; P = .066) in the 6 months following treatment in phase II.

PTVA patients also didn’t fare any better on Expanded Disability Status Scale (EDSS) scores, Multiple Sclerosis Functional Composite scores, 6-minute walk tests, or measures of cognition and quality of life.

"We chose very active patients who had one relapse in the previous year or [gadolinium-] enhancing lesions in the 3 months before. The sample size is small, but [more than half] of patients in the treatment group showed increased activity," Dr. Zivadinov said.

The majority of the subjects were women. On average, they were about 45 years old, had been diagnosed with MS for 11 years, and were mildly to moderately disabled (mean EDSS score about 4). Most were on interferon, glatiramer acetate, or both.

Venous angioplasty didn’t cause any serious complications, and it restored venous outflow to at least 50% of normal in most patients. Phase I patients had a better than 75% improvement overall. Phase II patients had less benefit; there were no differences in venous hemodynamic insufficiency scores between treated and sham patients.

The treatment "failed to provide any sustained improvement in venous outflow as measured through duplex and/or clinical and MRI outcomes," and "more sizable changes in venous outflow [were] associated with increased disease activity primarily noted on MRI," Dr. Zivadinov and his colleagues concluded.

The work was funded primarily by SUNY-Buffalo’s Neuroimaging Analysis Center and Baird MS Research Center. Dr. Zivadinov receives personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Bayer, Genzyme-Sanofi, Novartis, Bracco Imaging, and Questcor Pharmaceuticals.

aotto@frontlinemedcom.com

SAN DIEGO – Percutaneous transluminal venous angioplasty – also known as "liberation therapy" – doesn’t help people with multiple sclerosis and may increase MS brain activity in the short term, according to a small, randomized, sham-controlled trial from the State University of New York at Buffalo, the first randomized trial to investigate the procedure.

It "was ineffective in correcting" chronic cerebrospinal venous insufficiency (CCSVI), the recently described condition it targets. "The results ... caution against widespread adoption of venous angioplasty in the management of patients with MS outside of rigorous clinical trials," the investigators concluded.

The findings follow a recent Food and Drug Administration warning that PTVA (percutaneous transluminal venous angioplasty) can cause deaths and injuries, including strokes, damage to the treated vein, blood clots, cranial nerve damage, abdominal bleeding, and detachment and migration of stents.

The idea is to use balloon angioplasty and stents to widen veins in the chests and necks that appear to be narrowed in some MS patients. Proponents of the procedure say that those narrowed veins impair blood flow and lead to disease progression. The researchers who discovered the problem dubbed it CCSVI. A cottage industry has since sprung up to offer PTVA to MS patients.

The FDA noted in its warning that there have been no "controlled ... rigorously conducted, properly targeted" studies of the issue; that may have changed when Dr. Robert Zivadinov, a professor in the department of neurology at SUNY-Buffalo, presented his team’s findings at the annual meeting of the American Academy of Neurology.

"When you reopened those veins in the neck, I think something happened in reperfusing the brain and re-exacerbating disease activity. The message of this is clear. The majority of patients who are relapsing-remitting should not undergo this treatment," he said in an interview.

Ten patients got PTVA in the first phase of the study. The second phase randomized 9 to PTVA and 10 to a sham intervention. Most had relapsing-remitting MS.

There were no MS relapses in the first phase, but PTVA patients had more relapses (4 vs. 1; P = .389) and more MRI disease activity (cumulative number of new contrast-enhancing lesions (19 vs. 3; P = .062) and new T2 lesions (17 vs. 3; P = .066) in the 6 months following treatment in phase II.

PTVA patients also didn’t fare any better on Expanded Disability Status Scale (EDSS) scores, Multiple Sclerosis Functional Composite scores, 6-minute walk tests, or measures of cognition and quality of life.

"We chose very active patients who had one relapse in the previous year or [gadolinium-] enhancing lesions in the 3 months before. The sample size is small, but [more than half] of patients in the treatment group showed increased activity," Dr. Zivadinov said.

The majority of the subjects were women. On average, they were about 45 years old, had been diagnosed with MS for 11 years, and were mildly to moderately disabled (mean EDSS score about 4). Most were on interferon, glatiramer acetate, or both.

Venous angioplasty didn’t cause any serious complications, and it restored venous outflow to at least 50% of normal in most patients. Phase I patients had a better than 75% improvement overall. Phase II patients had less benefit; there were no differences in venous hemodynamic insufficiency scores between treated and sham patients.

The treatment "failed to provide any sustained improvement in venous outflow as measured through duplex and/or clinical and MRI outcomes," and "more sizable changes in venous outflow [were] associated with increased disease activity primarily noted on MRI," Dr. Zivadinov and his colleagues concluded.

The work was funded primarily by SUNY-Buffalo’s Neuroimaging Analysis Center and Baird MS Research Center. Dr. Zivadinov receives personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Bayer, Genzyme-Sanofi, Novartis, Bracco Imaging, and Questcor Pharmaceuticals.

aotto@frontlinemedcom.com

SAN DIEGO – Percutaneous transluminal venous angioplasty – also known as "liberation therapy" – doesn’t help people with multiple sclerosis and may increase MS brain activity in the short term, according to a small, randomized, sham-controlled trial from the State University of New York at Buffalo, the first randomized trial to investigate the procedure.

It "was ineffective in correcting" chronic cerebrospinal venous insufficiency (CCSVI), the recently described condition it targets. "The results ... caution against widespread adoption of venous angioplasty in the management of patients with MS outside of rigorous clinical trials," the investigators concluded.

The findings follow a recent Food and Drug Administration warning that PTVA (percutaneous transluminal venous angioplasty) can cause deaths and injuries, including strokes, damage to the treated vein, blood clots, cranial nerve damage, abdominal bleeding, and detachment and migration of stents.

The idea is to use balloon angioplasty and stents to widen veins in the chests and necks that appear to be narrowed in some MS patients. Proponents of the procedure say that those narrowed veins impair blood flow and lead to disease progression. The researchers who discovered the problem dubbed it CCSVI. A cottage industry has since sprung up to offer PTVA to MS patients.

The FDA noted in its warning that there have been no "controlled ... rigorously conducted, properly targeted" studies of the issue; that may have changed when Dr. Robert Zivadinov, a professor in the department of neurology at SUNY-Buffalo, presented his team’s findings at the annual meeting of the American Academy of Neurology.

"When you reopened those veins in the neck, I think something happened in reperfusing the brain and re-exacerbating disease activity. The message of this is clear. The majority of patients who are relapsing-remitting should not undergo this treatment," he said in an interview.

Ten patients got PTVA in the first phase of the study. The second phase randomized 9 to PTVA and 10 to a sham intervention. Most had relapsing-remitting MS.

There were no MS relapses in the first phase, but PTVA patients had more relapses (4 vs. 1; P = .389) and more MRI disease activity (cumulative number of new contrast-enhancing lesions (19 vs. 3; P = .062) and new T2 lesions (17 vs. 3; P = .066) in the 6 months following treatment in phase II.

PTVA patients also didn’t fare any better on Expanded Disability Status Scale (EDSS) scores, Multiple Sclerosis Functional Composite scores, 6-minute walk tests, or measures of cognition and quality of life.

"We chose very active patients who had one relapse in the previous year or [gadolinium-] enhancing lesions in the 3 months before. The sample size is small, but [more than half] of patients in the treatment group showed increased activity," Dr. Zivadinov said.

The majority of the subjects were women. On average, they were about 45 years old, had been diagnosed with MS for 11 years, and were mildly to moderately disabled (mean EDSS score about 4). Most were on interferon, glatiramer acetate, or both.

Venous angioplasty didn’t cause any serious complications, and it restored venous outflow to at least 50% of normal in most patients. Phase I patients had a better than 75% improvement overall. Phase II patients had less benefit; there were no differences in venous hemodynamic insufficiency scores between treated and sham patients.

The treatment "failed to provide any sustained improvement in venous outflow as measured through duplex and/or clinical and MRI outcomes," and "more sizable changes in venous outflow [were] associated with increased disease activity primarily noted on MRI," Dr. Zivadinov and his colleagues concluded.

The work was funded primarily by SUNY-Buffalo’s Neuroimaging Analysis Center and Baird MS Research Center. Dr. Zivadinov receives personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Bayer, Genzyme-Sanofi, Novartis, Bracco Imaging, and Questcor Pharmaceuticals.

aotto@frontlinemedcom.com

SAN DIEGO – Emerging skin and liver issues mean that daclizumab, a humanized monoclonal antibody in phase III testing for relapsing-remitting multiple sclerosis, likely will be a second-line agent if approved by the Food and Drug Administration, predicted Dr. Gavin Giovannoni, a neurology professor at the University of London.

There’s been one death from autoimmune hepatitis; researchers now monitor liver values monthly. There also have been a low number of serious cutaneous events, although no cases of Stevens-Johnson syndrome have been reported.

"Because of the skin reactions and the liver, I can’t see it coming out as a first-line drug for people with relapsing-remitting MS," Dr. Giovannoni said. It might prove to be a good alternative to natalizumab, he added, noting that daclizumab, if approved, likely would be on the market in 2016.

"If you don’t develop the skin reactions and the liver problem – if you get through that hurdle – the tolerability of this drug is very good," he said in an interview.

So far, daclizumab appears to be particularly good at slowing MS progression.

"It’s having a real impact on progression. Subanalysis of people with just minor relapses still got an impact on progression. The way this drug works is by boosting the innate immune system, so its impact on progression is out of proportion to its impact on relapses," he said.

That finding was confirmed in 2-year data that Dr. Giovannoni presented at the annual meeting of the American Academy of Neurology.

In that study, 170 patients who were on placebo during the first year were randomized to monthly 150 mg or 300 mg subcutaneous injections during the second year. The 52-week annualized relapse rate (ARR) was reduced by 59% among the former placebo patients who began taking daclizumab during year 2, compared with those who remained on placebo during year 2 (0.18 vs. 0.43; P less than .001), and the proportion of patients with confirmed 3-month disability progression was reduced by 50% (5% vs. 10%; P = .033).

The study included an additional 347 patients who spent the first year on daclizumab and were randomized to either continue their dose or resume it after a 24-week treatment interruption.

Those who stayed on the agent after the first year maintained their ARR in the second year (0.148 vs. 0.165) and had fewer new/newly enlarging T2 lesions (1.2 vs. 1.85; P = .032); 88% were free of confirmed disability progression at the end of 2 years. The treatment-interruption group showed no evidence of disease rebound.

The incidence of serious infections was about 2% in both years, and the incidence of serious cutaneous events was similar (1.1% vs. 1.0%). Aspartate aminotransferase/alanine aminotransferase elevations five times above the upper limit of normal were less common among daclizumab treated patients in year 2 (1.5% vs. 4%).

"The efficacy of [daclizumab] was sustained through the second year of therapy and the safety profile was similar in years 1 and 2," the researchers, led by Dr. Giovannoni, concluded.

He said the autoimmune hepatitis death, which occurred in the 300-mg treatment-interruption group, could have been caught in time and prevented with routine liver function monitoring.

There was also a case of asymptomatic glomerular nephritis in the trial that resolved when daclizumab was stopped, and one case of ulcerative colitis, which can’t be pinned on the drug because MS patients are at risk for inflammatory bowel disease, he said.

The skin problems "present on their own because the patients report them," he noted.

The study was funded by Biogen Idec and Abbott Biotherapeutics. Dr. Giovannoni disclosed personal compensation and research funding from Biogen, among other companies.

SAN DIEGO – Emerging skin and liver issues mean that daclizumab, a humanized monoclonal antibody in phase III testing for relapsing-remitting multiple sclerosis, likely will be a second-line agent if approved by the Food and Drug Administration, predicted Dr. Gavin Giovannoni, a neurology professor at the University of London.

There’s been one death from autoimmune hepatitis; researchers now monitor liver values monthly. There also have been a low number of serious cutaneous events, although no cases of Stevens-Johnson syndrome have been reported.

"Because of the skin reactions and the liver, I can’t see it coming out as a first-line drug for people with relapsing-remitting MS," Dr. Giovannoni said. It might prove to be a good alternative to natalizumab, he added, noting that daclizumab, if approved, likely would be on the market in 2016.

"If you don’t develop the skin reactions and the liver problem – if you get through that hurdle – the tolerability of this drug is very good," he said in an interview.

So far, daclizumab appears to be particularly good at slowing MS progression.

"It’s having a real impact on progression. Subanalysis of people with just minor relapses still got an impact on progression. The way this drug works is by boosting the innate immune system, so its impact on progression is out of proportion to its impact on relapses," he said.

That finding was confirmed in 2-year data that Dr. Giovannoni presented at the annual meeting of the American Academy of Neurology.

In that study, 170 patients who were on placebo during the first year were randomized to monthly 150 mg or 300 mg subcutaneous injections during the second year. The 52-week annualized relapse rate (ARR) was reduced by 59% among the former placebo patients who began taking daclizumab during year 2, compared with those who remained on placebo during year 2 (0.18 vs. 0.43; P less than .001), and the proportion of patients with confirmed 3-month disability progression was reduced by 50% (5% vs. 10%; P = .033).

The study included an additional 347 patients who spent the first year on daclizumab and were randomized to either continue their dose or resume it after a 24-week treatment interruption.

Those who stayed on the agent after the first year maintained their ARR in the second year (0.148 vs. 0.165) and had fewer new/newly enlarging T2 lesions (1.2 vs. 1.85; P = .032); 88% were free of confirmed disability progression at the end of 2 years. The treatment-interruption group showed no evidence of disease rebound.

The incidence of serious infections was about 2% in both years, and the incidence of serious cutaneous events was similar (1.1% vs. 1.0%). Aspartate aminotransferase/alanine aminotransferase elevations five times above the upper limit of normal were less common among daclizumab treated patients in year 2 (1.5% vs. 4%).

"The efficacy of [daclizumab] was sustained through the second year of therapy and the safety profile was similar in years 1 and 2," the researchers, led by Dr. Giovannoni, concluded.

He said the autoimmune hepatitis death, which occurred in the 300-mg treatment-interruption group, could have been caught in time and prevented with routine liver function monitoring.

There was also a case of asymptomatic glomerular nephritis in the trial that resolved when daclizumab was stopped, and one case of ulcerative colitis, which can’t be pinned on the drug because MS patients are at risk for inflammatory bowel disease, he said.

The skin problems "present on their own because the patients report them," he noted.

The study was funded by Biogen Idec and Abbott Biotherapeutics. Dr. Giovannoni disclosed personal compensation and research funding from Biogen, among other companies.

SAN DIEGO – Emerging skin and liver issues mean that daclizumab, a humanized monoclonal antibody in phase III testing for relapsing-remitting multiple sclerosis, likely will be a second-line agent if approved by the Food and Drug Administration, predicted Dr. Gavin Giovannoni, a neurology professor at the University of London.

There’s been one death from autoimmune hepatitis; researchers now monitor liver values monthly. There also have been a low number of serious cutaneous events, although no cases of Stevens-Johnson syndrome have been reported.

"Because of the skin reactions and the liver, I can’t see it coming out as a first-line drug for people with relapsing-remitting MS," Dr. Giovannoni said. It might prove to be a good alternative to natalizumab, he added, noting that daclizumab, if approved, likely would be on the market in 2016.

"If you don’t develop the skin reactions and the liver problem – if you get through that hurdle – the tolerability of this drug is very good," he said in an interview.

So far, daclizumab appears to be particularly good at slowing MS progression.

"It’s having a real impact on progression. Subanalysis of people with just minor relapses still got an impact on progression. The way this drug works is by boosting the innate immune system, so its impact on progression is out of proportion to its impact on relapses," he said.

That finding was confirmed in 2-year data that Dr. Giovannoni presented at the annual meeting of the American Academy of Neurology.

In that study, 170 patients who were on placebo during the first year were randomized to monthly 150 mg or 300 mg subcutaneous injections during the second year. The 52-week annualized relapse rate (ARR) was reduced by 59% among the former placebo patients who began taking daclizumab during year 2, compared with those who remained on placebo during year 2 (0.18 vs. 0.43; P less than .001), and the proportion of patients with confirmed 3-month disability progression was reduced by 50% (5% vs. 10%; P = .033).

The study included an additional 347 patients who spent the first year on daclizumab and were randomized to either continue their dose or resume it after a 24-week treatment interruption.

Those who stayed on the agent after the first year maintained their ARR in the second year (0.148 vs. 0.165) and had fewer new/newly enlarging T2 lesions (1.2 vs. 1.85; P = .032); 88% were free of confirmed disability progression at the end of 2 years. The treatment-interruption group showed no evidence of disease rebound.

The incidence of serious infections was about 2% in both years, and the incidence of serious cutaneous events was similar (1.1% vs. 1.0%). Aspartate aminotransferase/alanine aminotransferase elevations five times above the upper limit of normal were less common among daclizumab treated patients in year 2 (1.5% vs. 4%).

"The efficacy of [daclizumab] was sustained through the second year of therapy and the safety profile was similar in years 1 and 2," the researchers, led by Dr. Giovannoni, concluded.

He said the autoimmune hepatitis death, which occurred in the 300-mg treatment-interruption group, could have been caught in time and prevented with routine liver function monitoring.

There was also a case of asymptomatic glomerular nephritis in the trial that resolved when daclizumab was stopped, and one case of ulcerative colitis, which can’t be pinned on the drug because MS patients are at risk for inflammatory bowel disease, he said.

The skin problems "present on their own because the patients report them," he noted.

The study was funded by Biogen Idec and Abbott Biotherapeutics. Dr. Giovannoni disclosed personal compensation and research funding from Biogen, among other companies.

SAN DIEGO – Tube-shaped linear lesions seen on advanced MRI in people admitted to the emergency department for head injuries may not be diffuse axonal injury but rather evidence of bleeding due to mild traumatic brain injury, judging from preliminary results of a novel study.

"Not everything that we’re calling diffuse axonal injury is diffuse axonal injury," Dr. Gunjan Y. Parikh said in an interview during a poster session at the annual meeting of the American Academy of Neurology. "There may be, in fact, evidence under our noses of vascular injury. This has implications, and those patients should be followed very closely. If we can pinpoint that they’re a vascular injury in the acute setting, there are a lot of therapies [we can use] that target the vasculature."

Doug Brunk/IMNG Medical Media

Between October 2010 and October 2012 Dr. Parikh, a neuroimaging fellow at the National Institute of Neurological Disorders and Stroke, and his associates prospectively evaluated 256 patients enrolled in the Traumatic Head Injury Neuroimaging Classification (THINC) study who were admitted to the emergency department at Suburban Hospital in Bethesda, Md., and Washington (D.C.) Hospital Center after mild head injuries.

Administered by the Center for Neuroscience and Regenerative Medicine at Uniformed Services University in Bethesda, the THINC study protocol includes taking an MRI in subjects within 48 hours of presenting with acute head injury, with or without a positive diagnosis of concussion, and at up to three follow-up visits at 4, 30, and 90 days. The protocol includes T2-weighted MRI, fluid-attenuated inversion recovery (FLAIR), diffusion-weighted imaging (DWI), and three-dimensional tracking imaging (3-DTI).

The average age of the 256 patients was 50 years. Of these, 104 (41%) had imaging evidence of hemorrhage in the brain (67% reported loss of consciousness and 65% reported amnesia). These 104 patients underwent more detailed brain scans with advanced MRI within an average of 17 hours after the injury. This advanced imaging demonstrated that 20% of the 104 patients had microbleed lesions and 33% had tube-shaped linear lesions suggestive of vascular injury. Microbleeds were distributed throughout the brain, whereas linear lesions, which were found primarily in the anterior corona radiata, were more likely to be associated with injury to adjacent brain tissue.

"I was surprised that one-third of patients are having this linear type of lesion that we may think is vascular injury, and the majority of them – 91% – met the Glasgow Coma Scale criteria for mild TBI," Dr. Parikh commented. "These are patients who are usually sent home [after initial emergency department presentation]. I was also surprised to see so much evidence on other MRI sequences, proving that there is evidence of associated infarct or ischemia."

This type of analysis has not been done previously because "the logistical hurdles to imaging patients after any type of brain injury are so dramatic that it’s difficult to do this type of study," he said, emphasizing the preliminary nature of the work. "It was able to be done because of a unique collaboration between the National Institutes of Health (NIH) and the Department of Defense. If it weren’t for this collaboration, this would not have happened."

He noted that histopathological studies are "an important next step" to confirm the connection between the imaging markers and the pathology.

The study was supported by the NIH, the National Institute of Neurological Disorders and Stroke, and the Center for Neuroscience and Regenerative Medicine, a collaborative effort among the NIH, the Department of Defense, and Walter Reed National Military Medical Center, Bethesda. Dr. Parikh reported having no financial disclosures.

SAN DIEGO – Tube-shaped linear lesions seen on advanced MRI in people admitted to the emergency department for head injuries may not be diffuse axonal injury but rather evidence of bleeding due to mild traumatic brain injury, judging from preliminary results of a novel study.

"Not everything that we’re calling diffuse axonal injury is diffuse axonal injury," Dr. Gunjan Y. Parikh said in an interview during a poster session at the annual meeting of the American Academy of Neurology. "There may be, in fact, evidence under our noses of vascular injury. This has implications, and those patients should be followed very closely. If we can pinpoint that they’re a vascular injury in the acute setting, there are a lot of therapies [we can use] that target the vasculature."

Doug Brunk/IMNG Medical Media

Between October 2010 and October 2012 Dr. Parikh, a neuroimaging fellow at the National Institute of Neurological Disorders and Stroke, and his associates prospectively evaluated 256 patients enrolled in the Traumatic Head Injury Neuroimaging Classification (THINC) study who were admitted to the emergency department at Suburban Hospital in Bethesda, Md., and Washington (D.C.) Hospital Center after mild head injuries.

Administered by the Center for Neuroscience and Regenerative Medicine at Uniformed Services University in Bethesda, the THINC study protocol includes taking an MRI in subjects within 48 hours of presenting with acute head injury, with or without a positive diagnosis of concussion, and at up to three follow-up visits at 4, 30, and 90 days. The protocol includes T2-weighted MRI, fluid-attenuated inversion recovery (FLAIR), diffusion-weighted imaging (DWI), and three-dimensional tracking imaging (3-DTI).

The average age of the 256 patients was 50 years. Of these, 104 (41%) had imaging evidence of hemorrhage in the brain (67% reported loss of consciousness and 65% reported amnesia). These 104 patients underwent more detailed brain scans with advanced MRI within an average of 17 hours after the injury. This advanced imaging demonstrated that 20% of the 104 patients had microbleed lesions and 33% had tube-shaped linear lesions suggestive of vascular injury. Microbleeds were distributed throughout the brain, whereas linear lesions, which were found primarily in the anterior corona radiata, were more likely to be associated with injury to adjacent brain tissue.

"I was surprised that one-third of patients are having this linear type of lesion that we may think is vascular injury, and the majority of them – 91% – met the Glasgow Coma Scale criteria for mild TBI," Dr. Parikh commented. "These are patients who are usually sent home [after initial emergency department presentation]. I was also surprised to see so much evidence on other MRI sequences, proving that there is evidence of associated infarct or ischemia."

This type of analysis has not been done previously because "the logistical hurdles to imaging patients after any type of brain injury are so dramatic that it’s difficult to do this type of study," he said, emphasizing the preliminary nature of the work. "It was able to be done because of a unique collaboration between the National Institutes of Health (NIH) and the Department of Defense. If it weren’t for this collaboration, this would not have happened."

He noted that histopathological studies are "an important next step" to confirm the connection between the imaging markers and the pathology.

The study was supported by the NIH, the National Institute of Neurological Disorders and Stroke, and the Center for Neuroscience and Regenerative Medicine, a collaborative effort among the NIH, the Department of Defense, and Walter Reed National Military Medical Center, Bethesda. Dr. Parikh reported having no financial disclosures.

SAN DIEGO – Tube-shaped linear lesions seen on advanced MRI in people admitted to the emergency department for head injuries may not be diffuse axonal injury but rather evidence of bleeding due to mild traumatic brain injury, judging from preliminary results of a novel study.

"Not everything that we’re calling diffuse axonal injury is diffuse axonal injury," Dr. Gunjan Y. Parikh said in an interview during a poster session at the annual meeting of the American Academy of Neurology. "There may be, in fact, evidence under our noses of vascular injury. This has implications, and those patients should be followed very closely. If we can pinpoint that they’re a vascular injury in the acute setting, there are a lot of therapies [we can use] that target the vasculature."

Doug Brunk/IMNG Medical Media

Between October 2010 and October 2012 Dr. Parikh, a neuroimaging fellow at the National Institute of Neurological Disorders and Stroke, and his associates prospectively evaluated 256 patients enrolled in the Traumatic Head Injury Neuroimaging Classification (THINC) study who were admitted to the emergency department at Suburban Hospital in Bethesda, Md., and Washington (D.C.) Hospital Center after mild head injuries.

Administered by the Center for Neuroscience and Regenerative Medicine at Uniformed Services University in Bethesda, the THINC study protocol includes taking an MRI in subjects within 48 hours of presenting with acute head injury, with or without a positive diagnosis of concussion, and at up to three follow-up visits at 4, 30, and 90 days. The protocol includes T2-weighted MRI, fluid-attenuated inversion recovery (FLAIR), diffusion-weighted imaging (DWI), and three-dimensional tracking imaging (3-DTI).

The average age of the 256 patients was 50 years. Of these, 104 (41%) had imaging evidence of hemorrhage in the brain (67% reported loss of consciousness and 65% reported amnesia). These 104 patients underwent more detailed brain scans with advanced MRI within an average of 17 hours after the injury. This advanced imaging demonstrated that 20% of the 104 patients had microbleed lesions and 33% had tube-shaped linear lesions suggestive of vascular injury. Microbleeds were distributed throughout the brain, whereas linear lesions, which were found primarily in the anterior corona radiata, were more likely to be associated with injury to adjacent brain tissue.

"I was surprised that one-third of patients are having this linear type of lesion that we may think is vascular injury, and the majority of them – 91% – met the Glasgow Coma Scale criteria for mild TBI," Dr. Parikh commented. "These are patients who are usually sent home [after initial emergency department presentation]. I was also surprised to see so much evidence on other MRI sequences, proving that there is evidence of associated infarct or ischemia."

This type of analysis has not been done previously because "the logistical hurdles to imaging patients after any type of brain injury are so dramatic that it’s difficult to do this type of study," he said, emphasizing the preliminary nature of the work. "It was able to be done because of a unique collaboration between the National Institutes of Health (NIH) and the Department of Defense. If it weren’t for this collaboration, this would not have happened."

He noted that histopathological studies are "an important next step" to confirm the connection between the imaging markers and the pathology.

The study was supported by the NIH, the National Institute of Neurological Disorders and Stroke, and the Center for Neuroscience and Regenerative Medicine, a collaborative effort among the NIH, the Department of Defense, and Walter Reed National Military Medical Center, Bethesda. Dr. Parikh reported having no financial disclosures.

SAN DIEGO – Polyneuropathy affects an estimated 2.1% of the general population and about 10% of older adults, results from a large analysis demonstrated.

In addition, "surrogate markers of disability such as medication use, complications, and disabling symptoms seem to indicate that polyneuropathy confers significant disability," Dr. Christopher J. Klein said in an interview prior to the annual meeting of the American Academy of Neurology, where the research is scheduled to be presented March 21 by Dr. E. Matthew Hoffman, a PGY-2 resident in the neurology department at the Mayo Clinic, Rochester, Minn. "As the U.S. population ages and diabetes rates continue to rise, the disease burden of polyneuropathy will only increase."

Dr. Klein, of the division of peripheral nerve diseases in the neurology department at the Mayo Clinic, said that population-based epidemiologic studies of polyneuropathy and peripheral nerve diseases are lacking in terms of sampling completeness, population size, and generalizability. "As far as we can determine, there are no population-based estimates of disability related to polyneuropathy," he said.

To ascertain the disease burden of polyneuropathy, he and his associates evaluated data from the Rochester Epidemiology Project (REP), which links the population of Olmsted County, Minn., to electronically retrievable medical records of virtually all residents. The REP census generally has exceeded the U.S. Census since 1970, making population sampling very complete, Dr. Klein said.

In their analysis, the researchers studied 138,420 Olmsted County residents who received health care between 2006 and 2010, gathering five age- and gender-matched controls for each case with an ICD-9 code that implied a diffuse polyneuropathy, such as 337.0. They excluded 11,494 cases of isolated mononeuropathies, plexopathies, and radiculopathies.

More than half of the studied population (56%) had comprehensive neurologic examinations available by certified neurologists with retrievable neurology sheets documenting motor, reflex, and sensory deficits; gait difficulties; and other components of a comprehensive neurologic examination. Electronically retrievable nerve conduction studies were also available in 43% of the studied population. Information on medications, complications related to polyneuropathy, and answers to survey questions about disabling symptoms were extracted for cases and controls as surrogate markers to quantify functional disability.

Dr. Klein reported that 2,897 cases of polyneuropathy were identified, which translated into a prevalence of 2.1% for the entire population for the 5-year period. The prevalence rose with age and peaked in the eighth decade of life for both men (11.2%) and women (7.9%), which meant that about 10% of elderly overall were affected. Fifty percent of the polyneuropathy cases were idiopathic, followed by diabetic (38%), inflammatory (5%), hereditary (3%), toxic (3%), and other (1%).

The researchers observed many statistically significant increases in surrogate markers of disability, compared with the matched controls, including an eightfold increase in pain medication use; a fivefold increase in lower-limb ulcers; and up to a threefold increase in difficulties in gait, need for gait aids, and difficulties climbing stairs. This extent of witnessed surrogate marker disabilities is similar to what is observed with other major medical problems, said Dr. Klein, who is also co-editor of the Journal of the Peripheral Nervous System.

One limitation of the analysis, he noted, was that polyneuropathy cases were identified from ICD-9 codes. "Therefore, for most patients, symptomatic presentation is most likely and asymptomatic cases may not be documented, possibly leading to underestimation," Dr. Klein said.

The study was supported by the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, and the Mayo Foundation. Dr. Klein reported having no relevant financial disclosures.

dbrunk@frontlinemedcom.com

SAN DIEGO – Polyneuropathy affects an estimated 2.1% of the general population and about 10% of older adults, results from a large analysis demonstrated.

In addition, "surrogate markers of disability such as medication use, complications, and disabling symptoms seem to indicate that polyneuropathy confers significant disability," Dr. Christopher J. Klein said in an interview prior to the annual meeting of the American Academy of Neurology, where the research is scheduled to be presented March 21 by Dr. E. Matthew Hoffman, a PGY-2 resident in the neurology department at the Mayo Clinic, Rochester, Minn. "As the U.S. population ages and diabetes rates continue to rise, the disease burden of polyneuropathy will only increase."

Dr. Klein, of the division of peripheral nerve diseases in the neurology department at the Mayo Clinic, said that population-based epidemiologic studies of polyneuropathy and peripheral nerve diseases are lacking in terms of sampling completeness, population size, and generalizability. "As far as we can determine, there are no population-based estimates of disability related to polyneuropathy," he said.

To ascertain the disease burden of polyneuropathy, he and his associates evaluated data from the Rochester Epidemiology Project (REP), which links the population of Olmsted County, Minn., to electronically retrievable medical records of virtually all residents. The REP census generally has exceeded the U.S. Census since 1970, making population sampling very complete, Dr. Klein said.

In their analysis, the researchers studied 138,420 Olmsted County residents who received health care between 2006 and 2010, gathering five age- and gender-matched controls for each case with an ICD-9 code that implied a diffuse polyneuropathy, such as 337.0. They excluded 11,494 cases of isolated mononeuropathies, plexopathies, and radiculopathies.

More than half of the studied population (56%) had comprehensive neurologic examinations available by certified neurologists with retrievable neurology sheets documenting motor, reflex, and sensory deficits; gait difficulties; and other components of a comprehensive neurologic examination. Electronically retrievable nerve conduction studies were also available in 43% of the studied population. Information on medications, complications related to polyneuropathy, and answers to survey questions about disabling symptoms were extracted for cases and controls as surrogate markers to quantify functional disability.

Dr. Klein reported that 2,897 cases of polyneuropathy were identified, which translated into a prevalence of 2.1% for the entire population for the 5-year period. The prevalence rose with age and peaked in the eighth decade of life for both men (11.2%) and women (7.9%), which meant that about 10% of elderly overall were affected. Fifty percent of the polyneuropathy cases were idiopathic, followed by diabetic (38%), inflammatory (5%), hereditary (3%), toxic (3%), and other (1%).

The researchers observed many statistically significant increases in surrogate markers of disability, compared with the matched controls, including an eightfold increase in pain medication use; a fivefold increase in lower-limb ulcers; and up to a threefold increase in difficulties in gait, need for gait aids, and difficulties climbing stairs. This extent of witnessed surrogate marker disabilities is similar to what is observed with other major medical problems, said Dr. Klein, who is also co-editor of the Journal of the Peripheral Nervous System.

One limitation of the analysis, he noted, was that polyneuropathy cases were identified from ICD-9 codes. "Therefore, for most patients, symptomatic presentation is most likely and asymptomatic cases may not be documented, possibly leading to underestimation," Dr. Klein said.

The study was supported by the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, and the Mayo Foundation. Dr. Klein reported having no relevant financial disclosures.

dbrunk@frontlinemedcom.com

SAN DIEGO – Polyneuropathy affects an estimated 2.1% of the general population and about 10% of older adults, results from a large analysis demonstrated.

In addition, "surrogate markers of disability such as medication use, complications, and disabling symptoms seem to indicate that polyneuropathy confers significant disability," Dr. Christopher J. Klein said in an interview prior to the annual meeting of the American Academy of Neurology, where the research is scheduled to be presented March 21 by Dr. E. Matthew Hoffman, a PGY-2 resident in the neurology department at the Mayo Clinic, Rochester, Minn. "As the U.S. population ages and diabetes rates continue to rise, the disease burden of polyneuropathy will only increase."

Dr. Klein, of the division of peripheral nerve diseases in the neurology department at the Mayo Clinic, said that population-based epidemiologic studies of polyneuropathy and peripheral nerve diseases are lacking in terms of sampling completeness, population size, and generalizability. "As far as we can determine, there are no population-based estimates of disability related to polyneuropathy," he said.

To ascertain the disease burden of polyneuropathy, he and his associates evaluated data from the Rochester Epidemiology Project (REP), which links the population of Olmsted County, Minn., to electronically retrievable medical records of virtually all residents. The REP census generally has exceeded the U.S. Census since 1970, making population sampling very complete, Dr. Klein said.

In their analysis, the researchers studied 138,420 Olmsted County residents who received health care between 2006 and 2010, gathering five age- and gender-matched controls for each case with an ICD-9 code that implied a diffuse polyneuropathy, such as 337.0. They excluded 11,494 cases of isolated mononeuropathies, plexopathies, and radiculopathies.

More than half of the studied population (56%) had comprehensive neurologic examinations available by certified neurologists with retrievable neurology sheets documenting motor, reflex, and sensory deficits; gait difficulties; and other components of a comprehensive neurologic examination. Electronically retrievable nerve conduction studies were also available in 43% of the studied population. Information on medications, complications related to polyneuropathy, and answers to survey questions about disabling symptoms were extracted for cases and controls as surrogate markers to quantify functional disability.

Dr. Klein reported that 2,897 cases of polyneuropathy were identified, which translated into a prevalence of 2.1% for the entire population for the 5-year period. The prevalence rose with age and peaked in the eighth decade of life for both men (11.2%) and women (7.9%), which meant that about 10% of elderly overall were affected. Fifty percent of the polyneuropathy cases were idiopathic, followed by diabetic (38%), inflammatory (5%), hereditary (3%), toxic (3%), and other (1%).

The researchers observed many statistically significant increases in surrogate markers of disability, compared with the matched controls, including an eightfold increase in pain medication use; a fivefold increase in lower-limb ulcers; and up to a threefold increase in difficulties in gait, need for gait aids, and difficulties climbing stairs. This extent of witnessed surrogate marker disabilities is similar to what is observed with other major medical problems, said Dr. Klein, who is also co-editor of the Journal of the Peripheral Nervous System.

One limitation of the analysis, he noted, was that polyneuropathy cases were identified from ICD-9 codes. "Therefore, for most patients, symptomatic presentation is most likely and asymptomatic cases may not be documented, possibly leading to underestimation," Dr. Klein said.

The study was supported by the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, and the Mayo Foundation. Dr. Klein reported having no relevant financial disclosures.

dbrunk@frontlinemedcom.com

SAN DIEGO – It seems okay to switch patients with relapsing-remitting multiple sclerosis to 40-mg glatiramer acetate injections three times a week if the usual 20-mg daily injections get to be too much, according to Dr. Omar Khan, interim chair of the neurology department at Wayne State University in Detroit.

"Our patients love what the molecule does" for them, but some want to quit if the daily shots cause too much lipoatrophy or too many injection-site reactions. "I tell them rather than going off it, go every other day. [That] alternative is okay," he said in an interview.

The assertion is based in part on the randomized, blinded GALA (Glatiramer Acetate Low Frequency Administration Study), which Dr. Khan led and presented at the annual meeting of the American Academy of Neurology.

The trial randomized 943 relapsing-remitting multiple sclerosis patients to 40 mg of subcutaneous glatiramer acetate (Copaxone) three times weekly and 461 patients to matched placebo injections.

After a year, the placebo patients had an annualized relapse rate of 0.505, compared with a rate of 0.331 for the glatiramer acetate (GA) patients, a 34.4% reduction (P less than .0001). Similarly, the cumulative number of new or enlarging T2 lesions was 34.7% lower in the GA group, and the cumulative number of enhancing T1 lesions was 44.8% lower (P less than .0001 for both).

Although the trial did not pit 20 mg daily against 40 mg three times a week, Dr. Khan noted that the cumulative weekly dose is similar in both regimens, and that the response seen in the 40-mg group was comparable to what would be expected with 20 mg daily.

Injection-site redness, itching, and pain were more common in the GA group, as were headaches; 8.9% of the GA patients and 6.7% of the placebo patients left the study. Those results are also consistent with 20-mg daily injections.

There were no significant baseline differences between the groups. About 70% of the patients were women, they were about 38 years old on average, and almost all were white. The mean baseline Expanded Disability Status Scale score was about 2.7 in both arms, and patients were about 8 years out from diagnosis. The GA group had a baseline T2 lesion load of 19.7 mL, while the placebo group a baseline load of 17.4 mL.

It had been at least 2 years since any of the subjects had monoclonal antibodies, at least 6 months since they had used systemic corticosteroids, and at least 2 months since using immunomodulators. All the patients were GA naïve. The majority were from eastern Europe.

"We have a small phase II immunologic study," Dr. Khan noted, that pitted 20 mg daily against 40 mg every other day. "There were a lot of advantages of taking it every other day" – fewer injection-site reactions and the like – and "immunologically there was no difference" between the two regimens, he said. The study hasn’t been published yet.

In general, "if you look at just your general clinical observations, you can’t tell" which regimen patients are using, he said.

There’s debate about whether it’s better to start patients on a daily regimen, or if it’s okay to go with less frequent injections right out of the gate.

"You might generate a better Th2 [T-cell] shift if you keep them on every day for a few months, and then alter them. It could be true. The fact is that that sample in a large cohort does not exist. [Either way,] it doesn’t change a whole lot because at 6 months [and] 12 months everybody is doing well," Dr. Khan said.

In the meantime, "many of our patients routinely take [GA] less than every other day. They skip weekends; they create their own regimens," he said.

Teva Pharmaceuticals, the maker of GA, paid for the study. Dr. Khan has received personal compensation and research support from Teva, Biogen-Idec, and other companies.

aotto@frontlinemedcom.com

SAN DIEGO – It seems okay to switch patients with relapsing-remitting multiple sclerosis to 40-mg glatiramer acetate injections three times a week if the usual 20-mg daily injections get to be too much, according to Dr. Omar Khan, interim chair of the neurology department at Wayne State University in Detroit.

"Our patients love what the molecule does" for them, but some want to quit if the daily shots cause too much lipoatrophy or too many injection-site reactions. "I tell them rather than going off it, go every other day. [That] alternative is okay," he said in an interview.

The assertion is based in part on the randomized, blinded GALA (Glatiramer Acetate Low Frequency Administration Study), which Dr. Khan led and presented at the annual meeting of the American Academy of Neurology.

The trial randomized 943 relapsing-remitting multiple sclerosis patients to 40 mg of subcutaneous glatiramer acetate (Copaxone) three times weekly and 461 patients to matched placebo injections.

After a year, the placebo patients had an annualized relapse rate of 0.505, compared with a rate of 0.331 for the glatiramer acetate (GA) patients, a 34.4% reduction (P less than .0001). Similarly, the cumulative number of new or enlarging T2 lesions was 34.7% lower in the GA group, and the cumulative number of enhancing T1 lesions was 44.8% lower (P less than .0001 for both).

Although the trial did not pit 20 mg daily against 40 mg three times a week, Dr. Khan noted that the cumulative weekly dose is similar in both regimens, and that the response seen in the 40-mg group was comparable to what would be expected with 20 mg daily.

Injection-site redness, itching, and pain were more common in the GA group, as were headaches; 8.9% of the GA patients and 6.7% of the placebo patients left the study. Those results are also consistent with 20-mg daily injections.

There were no significant baseline differences between the groups. About 70% of the patients were women, they were about 38 years old on average, and almost all were white. The mean baseline Expanded Disability Status Scale score was about 2.7 in both arms, and patients were about 8 years out from diagnosis. The GA group had a baseline T2 lesion load of 19.7 mL, while the placebo group a baseline load of 17.4 mL.

It had been at least 2 years since any of the subjects had monoclonal antibodies, at least 6 months since they had used systemic corticosteroids, and at least 2 months since using immunomodulators. All the patients were GA naïve. The majority were from eastern Europe.

"We have a small phase II immunologic study," Dr. Khan noted, that pitted 20 mg daily against 40 mg every other day. "There were a lot of advantages of taking it every other day" – fewer injection-site reactions and the like – and "immunologically there was no difference" between the two regimens, he said. The study hasn’t been published yet.

In general, "if you look at just your general clinical observations, you can’t tell" which regimen patients are using, he said.

There’s debate about whether it’s better to start patients on a daily regimen, or if it’s okay to go with less frequent injections right out of the gate.

"You might generate a better Th2 [T-cell] shift if you keep them on every day for a few months, and then alter them. It could be true. The fact is that that sample in a large cohort does not exist. [Either way,] it doesn’t change a whole lot because at 6 months [and] 12 months everybody is doing well," Dr. Khan said.

In the meantime, "many of our patients routinely take [GA] less than every other day. They skip weekends; they create their own regimens," he said.

Teva Pharmaceuticals, the maker of GA, paid for the study. Dr. Khan has received personal compensation and research support from Teva, Biogen-Idec, and other companies.

aotto@frontlinemedcom.com

SAN DIEGO – It seems okay to switch patients with relapsing-remitting multiple sclerosis to 40-mg glatiramer acetate injections three times a week if the usual 20-mg daily injections get to be too much, according to Dr. Omar Khan, interim chair of the neurology department at Wayne State University in Detroit.

"Our patients love what the molecule does" for them, but some want to quit if the daily shots cause too much lipoatrophy or too many injection-site reactions. "I tell them rather than going off it, go every other day. [That] alternative is okay," he said in an interview.

The assertion is based in part on the randomized, blinded GALA (Glatiramer Acetate Low Frequency Administration Study), which Dr. Khan led and presented at the annual meeting of the American Academy of Neurology.

The trial randomized 943 relapsing-remitting multiple sclerosis patients to 40 mg of subcutaneous glatiramer acetate (Copaxone) three times weekly and 461 patients to matched placebo injections.

After a year, the placebo patients had an annualized relapse rate of 0.505, compared with a rate of 0.331 for the glatiramer acetate (GA) patients, a 34.4% reduction (P less than .0001). Similarly, the cumulative number of new or enlarging T2 lesions was 34.7% lower in the GA group, and the cumulative number of enhancing T1 lesions was 44.8% lower (P less than .0001 for both).

Although the trial did not pit 20 mg daily against 40 mg three times a week, Dr. Khan noted that the cumulative weekly dose is similar in both regimens, and that the response seen in the 40-mg group was comparable to what would be expected with 20 mg daily.

Injection-site redness, itching, and pain were more common in the GA group, as were headaches; 8.9% of the GA patients and 6.7% of the placebo patients left the study. Those results are also consistent with 20-mg daily injections.

There were no significant baseline differences between the groups. About 70% of the patients were women, they were about 38 years old on average, and almost all were white. The mean baseline Expanded Disability Status Scale score was about 2.7 in both arms, and patients were about 8 years out from diagnosis. The GA group had a baseline T2 lesion load of 19.7 mL, while the placebo group a baseline load of 17.4 mL.

It had been at least 2 years since any of the subjects had monoclonal antibodies, at least 6 months since they had used systemic corticosteroids, and at least 2 months since using immunomodulators. All the patients were GA naïve. The majority were from eastern Europe.

"We have a small phase II immunologic study," Dr. Khan noted, that pitted 20 mg daily against 40 mg every other day. "There were a lot of advantages of taking it every other day" – fewer injection-site reactions and the like – and "immunologically there was no difference" between the two regimens, he said. The study hasn’t been published yet.

In general, "if you look at just your general clinical observations, you can’t tell" which regimen patients are using, he said.

There’s debate about whether it’s better to start patients on a daily regimen, or if it’s okay to go with less frequent injections right out of the gate.

"You might generate a better Th2 [T-cell] shift if you keep them on every day for a few months, and then alter them. It could be true. The fact is that that sample in a large cohort does not exist. [Either way,] it doesn’t change a whole lot because at 6 months [and] 12 months everybody is doing well," Dr. Khan said.

In the meantime, "many of our patients routinely take [GA] less than every other day. They skip weekends; they create their own regimens," he said.

Teva Pharmaceuticals, the maker of GA, paid for the study. Dr. Khan has received personal compensation and research support from Teva, Biogen-Idec, and other companies.

aotto@frontlinemedcom.com