Jeff Evans

BETHESDA, MD. — Current knowledge about the epidemiology of Alzheimer's disease and cognitive decline has not provided enough evidence to recommend specific, preventive interventions, according to a draft “state-of-the-science” report issued by a panel of experts assembled by the National Institutes of Health.

The 15-member panel found that there is not enough clinical evidence to support the use of pharmaceutical agents or dietary supplements to prevent cognitive decline or Alzheimer's disease, but ongoing additional studies of antihypertensive medications, omega-3 fatty acids, physical activity, and cognitive engagement “may provide new insight into the prevention of delay of cognitive decline or Alzheimer's disease.”

“We're hoping that our report is going to supply physicians with accurate information that they can give to their patients” to clarify what interventions may be worth continuing or pursuing and which should be discontinued, panelist Dr. Carl C. Bell, director of the Institute for Juvenile Research in the department of psychiatry at the University of Illinois at Chicago, said at a press telebriefing.

A wide range of modifiable factors has been reported to be associated with risk for Alzheimer's disease, such as diabetes, elevated blood cholesterol in midlife, and depression, but also relatively benign changes in diet, medication, or lifestyle.

However, the overall quality of evidence from these studies is low, the panel said, and they did not find enough evidence to draw firm conclusions about the association of modifiable risk factors with cognitive decline or Alzheimer's disease.

In light of the fact that there are no proven interventions that prevent cognitive decline or Alzheimer's disease, panel member Arnold L. Potosky, Ph.D., of Georgetown University in Washington said that it is important for physicians to discuss participation in clinical studies with their patients.

The panel recommended that further research should include:

▸ The development and use of rigorous, consensus-based diagnostic criteria for Alzheimer's disease and mild cognitive impairment.

▸ The development and use of a standardized, well-validated, and culturally sensitive battery of outcome measures across research studies.

▸ The collection of data from caregivers of people with mild cognitive impairment or early Alzheimer's disease in a systematic manner in observational studies and randomized, controlled trials.

▸ The conduct of large-scale, long-term population-based studies with well-validated exposure and outcome measures in people followed from middle to old age. Existing cohorts from ongoing studies of this type also could be explored for timely, cost-effective identification of individuals at high risk of cognitive decline or Alzheimer's disease.

▸ The leveraging of alternative research resources and platforms that facilitate long-term longitudinal assessments, such as a multicenter Alzheimer's disease registry or observational studies within large health care delivery systems with defined populations and well-developed electronic health records.

▸ The creation of a simple, inexpensive, quantitative instrument that can be administered by a trained nonexpert to assess change in cognitive status over time.

The scope of the statement was restricted to studies of people aged 50 years or older that were conducted in developed countries. The minimum sample size in these studied was at least 50 patients in randomized, controlled trials and at least 300 patients in observational studies.

The duration between exposure to a preventive intervention and study outcomes had to be at least 1 year for studies of mild cognitive impairment and at least 2 years for studies of Alzheimer's disease.

The panel based their draft statement on an evidence report from the Evidence-Based Practice Center at Duke University's Clinical Research Institute, which was commissioned by the Agency for Healthcare Research and Quality.

The evidence report is available at www.ahrq.gov/clinic/tp/alzcogtp.htmconsensus.nih.gov

The report should clarify what interventions may be worth continuing and which should be discontinued.

Source DR. BELL

BETHESDA, MD. — Current knowledge about the epidemiology of Alzheimer's disease and cognitive decline has not provided enough evidence to recommend specific, preventive interventions, according to a draft “state-of-the-science” report issued by a panel of experts assembled by the National Institutes of Health.

The 15-member panel found that there is not enough clinical evidence to support the use of pharmaceutical agents or dietary supplements to prevent cognitive decline or Alzheimer's disease, but ongoing additional studies of antihypertensive medications, omega-3 fatty acids, physical activity, and cognitive engagement “may provide new insight into the prevention of delay of cognitive decline or Alzheimer's disease.”

“We're hoping that our report is going to supply physicians with accurate information that they can give to their patients” to clarify what interventions may be worth continuing or pursuing and which should be discontinued, panelist Dr. Carl C. Bell, director of the Institute for Juvenile Research in the department of psychiatry at the University of Illinois at Chicago, said at a press telebriefing.

A wide range of modifiable factors has been reported to be associated with risk for Alzheimer's disease, such as diabetes, elevated blood cholesterol in midlife, and depression, but also relatively benign changes in diet, medication, or lifestyle.

However, the overall quality of evidence from these studies is low, the panel said, and they did not find enough evidence to draw firm conclusions about the association of modifiable risk factors with cognitive decline or Alzheimer's disease.

In light of the fact that there are no proven interventions that prevent cognitive decline or Alzheimer's disease, panel member Arnold L. Potosky, Ph.D., of Georgetown University in Washington said that it is important for physicians to discuss participation in clinical studies with their patients.

The panel recommended that further research should include:

▸ The development and use of rigorous, consensus-based diagnostic criteria for Alzheimer's disease and mild cognitive impairment.

▸ The development and use of a standardized, well-validated, and culturally sensitive battery of outcome measures across research studies.

▸ The collection of data from caregivers of people with mild cognitive impairment or early Alzheimer's disease in a systematic manner in observational studies and randomized, controlled trials.

▸ The conduct of large-scale, long-term population-based studies with well-validated exposure and outcome measures in people followed from middle to old age. Existing cohorts from ongoing studies of this type also could be explored for timely, cost-effective identification of individuals at high risk of cognitive decline or Alzheimer's disease.

▸ The leveraging of alternative research resources and platforms that facilitate long-term longitudinal assessments, such as a multicenter Alzheimer's disease registry or observational studies within large health care delivery systems with defined populations and well-developed electronic health records.

▸ The creation of a simple, inexpensive, quantitative instrument that can be administered by a trained nonexpert to assess change in cognitive status over time.

The scope of the statement was restricted to studies of people aged 50 years or older that were conducted in developed countries. The minimum sample size in these studied was at least 50 patients in randomized, controlled trials and at least 300 patients in observational studies.

The duration between exposure to a preventive intervention and study outcomes had to be at least 1 year for studies of mild cognitive impairment and at least 2 years for studies of Alzheimer's disease.

The panel based their draft statement on an evidence report from the Evidence-Based Practice Center at Duke University's Clinical Research Institute, which was commissioned by the Agency for Healthcare Research and Quality.

The evidence report is available at www.ahrq.gov/clinic/tp/alzcogtp.htmconsensus.nih.gov

The report should clarify what interventions may be worth continuing and which should be discontinued.

Source DR. BELL

BETHESDA, MD. — Current knowledge about the epidemiology of Alzheimer's disease and cognitive decline has not provided enough evidence to recommend specific, preventive interventions, according to a draft “state-of-the-science” report issued by a panel of experts assembled by the National Institutes of Health.

The 15-member panel found that there is not enough clinical evidence to support the use of pharmaceutical agents or dietary supplements to prevent cognitive decline or Alzheimer's disease, but ongoing additional studies of antihypertensive medications, omega-3 fatty acids, physical activity, and cognitive engagement “may provide new insight into the prevention of delay of cognitive decline or Alzheimer's disease.”

“We're hoping that our report is going to supply physicians with accurate information that they can give to their patients” to clarify what interventions may be worth continuing or pursuing and which should be discontinued, panelist Dr. Carl C. Bell, director of the Institute for Juvenile Research in the department of psychiatry at the University of Illinois at Chicago, said at a press telebriefing.

A wide range of modifiable factors has been reported to be associated with risk for Alzheimer's disease, such as diabetes, elevated blood cholesterol in midlife, and depression, but also relatively benign changes in diet, medication, or lifestyle.

However, the overall quality of evidence from these studies is low, the panel said, and they did not find enough evidence to draw firm conclusions about the association of modifiable risk factors with cognitive decline or Alzheimer's disease.

In light of the fact that there are no proven interventions that prevent cognitive decline or Alzheimer's disease, panel member Arnold L. Potosky, Ph.D., of Georgetown University in Washington said that it is important for physicians to discuss participation in clinical studies with their patients.

The panel recommended that further research should include:

▸ The development and use of rigorous, consensus-based diagnostic criteria for Alzheimer's disease and mild cognitive impairment.

▸ The development and use of a standardized, well-validated, and culturally sensitive battery of outcome measures across research studies.

▸ The collection of data from caregivers of people with mild cognitive impairment or early Alzheimer's disease in a systematic manner in observational studies and randomized, controlled trials.

▸ The conduct of large-scale, long-term population-based studies with well-validated exposure and outcome measures in people followed from middle to old age. Existing cohorts from ongoing studies of this type also could be explored for timely, cost-effective identification of individuals at high risk of cognitive decline or Alzheimer's disease.

▸ The leveraging of alternative research resources and platforms that facilitate long-term longitudinal assessments, such as a multicenter Alzheimer's disease registry or observational studies within large health care delivery systems with defined populations and well-developed electronic health records.

▸ The creation of a simple, inexpensive, quantitative instrument that can be administered by a trained nonexpert to assess change in cognitive status over time.

The scope of the statement was restricted to studies of people aged 50 years or older that were conducted in developed countries. The minimum sample size in these studied was at least 50 patients in randomized, controlled trials and at least 300 patients in observational studies.

The duration between exposure to a preventive intervention and study outcomes had to be at least 1 year for studies of mild cognitive impairment and at least 2 years for studies of Alzheimer's disease.

The panel based their draft statement on an evidence report from the Evidence-Based Practice Center at Duke University's Clinical Research Institute, which was commissioned by the Agency for Healthcare Research and Quality.

The evidence report is available at www.ahrq.gov/clinic/tp/alzcogtp.htmconsensus.nih.gov

The report should clarify what interventions may be worth continuing and which should be discontinued.

Source DR. BELL

BETHESDA, MD. — Current knowledge about the epidemiology of Alzheimer's disease and cognitive decline has not provided enough evidence to recommend specific, preventive interventions, according to a draft “state-of-the-science” report issued by a panel of experts assembled by the National Institutes of Health.

The 15-member panel found that there is not enough evidence to support the use of pharmaceutical agents or dietary supplements to prevent cognitive decline or Alzheimer's disease, but ongoing additional studies of antihypertensive medications, omega-3 fatty acids, physical activity, and cognitive engagement “may provide new insight into the prevention or delay of cognitive decline or Alzheimer's disease.”

“We're hoping that our report is going to supply physicians with accurate information that they can give to their patients” to clarify what interventions may be worth continuing or pursuing and which should be discontinued, said panelist Dr. Carl C. Bell, director of the Institute for Juvenile Research in the department of psychiatry at the University of Illinois at Chicago, at a press telebriefing.

A wide range of modifiable factors have been reported to be associated with risk for Alzheimer's disease, such as diabetes, elevated blood cholesterol in midlife, and depression, but also relatively benign changes in diet, medication, or lifestyle. However, the overall quality of evidence from these studies is low, the panel said, and they did not find enough evidence to draw firm conclusions.

In light of the fact that there are no proven interventions that prevent cognitive decline or Alzheimer's disease, panel member Arnold L. Potosky, Ph.D., of Georgetown University in Washington said that it is important for physicians to discuss participation in clinical studies with their patients.

The panel recommended that further research should include:

▸ The development and use of rigorous, consensus-based diagnostic criteria for Alzheimer's disease and mild cognitive impairment.

▸ The development and use of a standardized, well-validated, and culturally sensitive battery of outcome measures across research studies.

▸ The collection of data from caregivers of people with mild cognitive impairment or early Alzheimer's disease in a systematic manner in observational studies and randomized, controlled trials.

▸ The conduct of large-scale, long-term population-based studies with well-validated exposure and outcome measures in people followed from middle to old age. Existing cohorts from ongoing studies of this type also could be explored for timely, cost-effective identification of individuals at high risk of cognitive decline or Alzheimer's disease.

▸ The leveraging of alternative research resources and platforms that facilitate long-term longitudinal assessments, such as a multicenter Alzheimer's disease registry or observational studies within large health care delivery systems with defined populations and well-developed electronic health records.

▸ The creation of a simple, inexpensive, quantitative instrument that can be administered by a trained nonexpert to assess change in cognitive status over time.

The scope of the statement was restricted to studies of people aged 50 years or older that were conducted in developed countries. The minimum sample size in these studied was at least 50 patients in randomized, controlled trials and at least 300 patients in observational studies. The duration between exposure to a preventive intervention and study outcomes had to be at least 1 year for studies of mild cognitive impairment and at least 2 years for studies of Alzheimer's disease.

The panel based their draft statement on an evidence report from the Evidence-Based Practice Center at Duke University's Clinical Research Institute, which was commissioned by the Agency for Healthcare Research and Quality.

The evidence report is available at www.ahrq.gov/clinic/tp/alzcogtp.htmconsensus.nih.gov

BETHESDA, MD. — Current knowledge about the epidemiology of Alzheimer's disease and cognitive decline has not provided enough evidence to recommend specific, preventive interventions, according to a draft “state-of-the-science” report issued by a panel of experts assembled by the National Institutes of Health.

The 15-member panel found that there is not enough evidence to support the use of pharmaceutical agents or dietary supplements to prevent cognitive decline or Alzheimer's disease, but ongoing additional studies of antihypertensive medications, omega-3 fatty acids, physical activity, and cognitive engagement “may provide new insight into the prevention or delay of cognitive decline or Alzheimer's disease.”

“We're hoping that our report is going to supply physicians with accurate information that they can give to their patients” to clarify what interventions may be worth continuing or pursuing and which should be discontinued, said panelist Dr. Carl C. Bell, director of the Institute for Juvenile Research in the department of psychiatry at the University of Illinois at Chicago, at a press telebriefing.

A wide range of modifiable factors have been reported to be associated with risk for Alzheimer's disease, such as diabetes, elevated blood cholesterol in midlife, and depression, but also relatively benign changes in diet, medication, or lifestyle. However, the overall quality of evidence from these studies is low, the panel said, and they did not find enough evidence to draw firm conclusions.

In light of the fact that there are no proven interventions that prevent cognitive decline or Alzheimer's disease, panel member Arnold L. Potosky, Ph.D., of Georgetown University in Washington said that it is important for physicians to discuss participation in clinical studies with their patients.

The panel recommended that further research should include:

▸ The development and use of rigorous, consensus-based diagnostic criteria for Alzheimer's disease and mild cognitive impairment.

▸ The development and use of a standardized, well-validated, and culturally sensitive battery of outcome measures across research studies.

▸ The collection of data from caregivers of people with mild cognitive impairment or early Alzheimer's disease in a systematic manner in observational studies and randomized, controlled trials.

▸ The conduct of large-scale, long-term population-based studies with well-validated exposure and outcome measures in people followed from middle to old age. Existing cohorts from ongoing studies of this type also could be explored for timely, cost-effective identification of individuals at high risk of cognitive decline or Alzheimer's disease.

▸ The leveraging of alternative research resources and platforms that facilitate long-term longitudinal assessments, such as a multicenter Alzheimer's disease registry or observational studies within large health care delivery systems with defined populations and well-developed electronic health records.

▸ The creation of a simple, inexpensive, quantitative instrument that can be administered by a trained nonexpert to assess change in cognitive status over time.

The scope of the statement was restricted to studies of people aged 50 years or older that were conducted in developed countries. The minimum sample size in these studied was at least 50 patients in randomized, controlled trials and at least 300 patients in observational studies. The duration between exposure to a preventive intervention and study outcomes had to be at least 1 year for studies of mild cognitive impairment and at least 2 years for studies of Alzheimer's disease.

The panel based their draft statement on an evidence report from the Evidence-Based Practice Center at Duke University's Clinical Research Institute, which was commissioned by the Agency for Healthcare Research and Quality.

The evidence report is available at www.ahrq.gov/clinic/tp/alzcogtp.htmconsensus.nih.gov

BETHESDA, MD. — Current knowledge about the epidemiology of Alzheimer's disease and cognitive decline has not provided enough evidence to recommend specific, preventive interventions, according to a draft “state-of-the-science” report issued by a panel of experts assembled by the National Institutes of Health.

The 15-member panel found that there is not enough evidence to support the use of pharmaceutical agents or dietary supplements to prevent cognitive decline or Alzheimer's disease, but ongoing additional studies of antihypertensive medications, omega-3 fatty acids, physical activity, and cognitive engagement “may provide new insight into the prevention or delay of cognitive decline or Alzheimer's disease.”

“We're hoping that our report is going to supply physicians with accurate information that they can give to their patients” to clarify what interventions may be worth continuing or pursuing and which should be discontinued, said panelist Dr. Carl C. Bell, director of the Institute for Juvenile Research in the department of psychiatry at the University of Illinois at Chicago, at a press telebriefing.

A wide range of modifiable factors have been reported to be associated with risk for Alzheimer's disease, such as diabetes, elevated blood cholesterol in midlife, and depression, but also relatively benign changes in diet, medication, or lifestyle. However, the overall quality of evidence from these studies is low, the panel said, and they did not find enough evidence to draw firm conclusions.

In light of the fact that there are no proven interventions that prevent cognitive decline or Alzheimer's disease, panel member Arnold L. Potosky, Ph.D., of Georgetown University in Washington said that it is important for physicians to discuss participation in clinical studies with their patients.

The panel recommended that further research should include:

▸ The development and use of rigorous, consensus-based diagnostic criteria for Alzheimer's disease and mild cognitive impairment.

▸ The development and use of a standardized, well-validated, and culturally sensitive battery of outcome measures across research studies.

▸ The collection of data from caregivers of people with mild cognitive impairment or early Alzheimer's disease in a systematic manner in observational studies and randomized, controlled trials.

▸ The conduct of large-scale, long-term population-based studies with well-validated exposure and outcome measures in people followed from middle to old age. Existing cohorts from ongoing studies of this type also could be explored for timely, cost-effective identification of individuals at high risk of cognitive decline or Alzheimer's disease.

▸ The leveraging of alternative research resources and platforms that facilitate long-term longitudinal assessments, such as a multicenter Alzheimer's disease registry or observational studies within large health care delivery systems with defined populations and well-developed electronic health records.

▸ The creation of a simple, inexpensive, quantitative instrument that can be administered by a trained nonexpert to assess change in cognitive status over time.

The scope of the statement was restricted to studies of people aged 50 years or older that were conducted in developed countries. The minimum sample size in these studied was at least 50 patients in randomized, controlled trials and at least 300 patients in observational studies. The duration between exposure to a preventive intervention and study outcomes had to be at least 1 year for studies of mild cognitive impairment and at least 2 years for studies of Alzheimer's disease.

The panel based their draft statement on an evidence report from the Evidence-Based Practice Center at Duke University's Clinical Research Institute, which was commissioned by the Agency for Healthcare Research and Quality.

The evidence report is available at www.ahrq.gov/clinic/tp/alzcogtp.htmconsensus.nih.gov

Major Finding: Measurement of quality of life with the PDQ-39 after 1 year improved significantly more in DBS patients than in medical therapy patients (−5.0 vs. −0.3).

Data Source: A randomized, open-label trial of 366 patients with Parkinson's disease.

Disclosures: Trial was funded by the U.K. Medical Research Council, Parkinson's U.K., and the U.K. Department of Health. Dr. Wheatley and most coauthors had no relevant disclosures. One coauthor received grants and fees from Medtronic for another similar study. Dr. Rodriguez-Oroz reported relationships with Medtronic and several companies that manufacture dopaminergic agents.

Parkinson's disease patients report better quality of life after 1 year of deep brain stimulation than with best medical therapy, according to the largest randomized trial of the two treatment options for patients with advanced disease.

In the PD SURG trial, deep brain stimulation (DBS) resulted in greater improvement in motor function scores and complications of therapy, as well as lower use of dopaminergic drugs, than did best medical therapy. However, both arms of the open-label study experienced a similar amount of cognitive decline, with significantly poorer function in verbal fluency and vocabulary in DBS patients.

The trial largely corroborates the results observed in two previous trials of DBS vs. best medical therapy that recorded follow-up out to 6 months (N. Engl. J. Med. 2006;355:896–908; JAMA 2009;301:63–73).

“Surgery is likely to remain an important treatment option for patients with PD, especially if the way in which deep brain stimulation exerts its therapeutic benefits is better understood, if its use can be optimised by better electrode placement and settings, and if patients who would have the greatest benefit can be better identified,” Dr. Keith Wheatley of the University of Birmingham (England) and his colleagues concluded (Lancet Neurol. 2010 April 29 [doi:10.1016/S1474-4422(10)70093-4

During 2000-2006, Dr. Wheatley and his associates randomized 366 patients evenly to either treatment group at 13 neurosurgical centers in the United Kingdom. The patients had a mean age of 59 years and were mostly men (about 70%) with a mean disease duration of 11.4 years. In each group, 45 patients were taking apomorphine at study entry; 145 total were taking it before the study.

Of 178 patients who underwent surgery, DBS targeted the subthalamic nucleus in 174 and the globus pallidus pars interna in 4. All but two of the surgeries were bilateral. A total of 12 patients in the best medical therapy arm underwent DBS surgery between baseline and 1 year but were analyzed in the medical therapy arm anyway.

Measurement of quality of life with the Parkinson's Disease Questionnaire (PDQ-39) after 1 year—the primary outcome—improved significantly more in DBS patients than in medical therapy patients (−5.0 vs. −0.3).

During “on” periods, the mean United Parkinson's Disease Rating Scale (UPDRS) total score after 1 year improved by a mean of 6.6 points in the surgery group and worsened by 1.6 points in the medical therapy group, which was a significant difference. In “off” time, UPDRS scores improved significantly more in DBS patients (−27.4) than in medical therapy patients (−0.9 points).

Cognitive status measured with the Dementia Rating Scale-II (DRS-II) declined by 0.4 points in each group after 1 year. Neuropsychological testing in a subset of patients revealed that verbal fluency and vocabulary had declined after 1 year significantly more in patients who had undergone surgery than in patients who took medication alone.

Treatment with DBS also resulted in a significantly lower mean levodopa equivalent dose after 1 year than did medical therapy alone (894 vs. 1,347 mg/day).

“The cost of surgery will be partly offset by the reduction in the amount of drug therapy required by patients who have had surgery. In particular, if apomorphine or continuous intestinal infusions of levodopa, with high recurrent costs, are the alternative drug treatment options, the cost-effectiveness equation might favor surgery … thus, it is important to identify patients who are or are not likely to benefit from surgery when the risks and costs are taken into account,” they wrote.

Overall, 36 surgery patients experienced 43 serious adverse events, including 16 infections. In the surgery group, 25 Parkinson's disease–related and drug-related serious adverse events occurred in 20 patients, compared with 14 events in 13 medical therapy patients. The two remaining serious adverse events in the group included one unsuccessful postoperative suicide and one death from hemorrhage during surgery.

The trial has a number of strengths that improved on previous trials, including a larger number of patients, a longer follow-up, and treatment with continuous infusions of apomorphine, Dr. Maria C. Rodriguez-Oroz wrote in an editorial (Lancet Neurol. 2010 April 29 [doi:10.1016/S1474-4422(10)70108-3

Dr. Rodriguez-Oroz of the Clinica Universidad de Navarra, Pamplona, Spain, added that some limitations of the trial raise questions about the results. For example, neither patients nor evaluators were masked to treatment. Evaluations of dyskinesia and “off” period time could have been done with a more reliable tool than the complications of therapy subsection of the UPDRS. Investigators made their own judgment about whether a patient was in the “on” state (without assessment of inter-rater reliability). The DRS-II might be inadequate to assess cognitive ability in Parkinson's. And the investigators did not record nonserious adverse events.

Major Finding: Measurement of quality of life with the PDQ-39 after 1 year improved significantly more in DBS patients than in medical therapy patients (−5.0 vs. −0.3).

Data Source: A randomized, open-label trial of 366 patients with Parkinson's disease.

Disclosures: Trial was funded by the U.K. Medical Research Council, Parkinson's U.K., and the U.K. Department of Health. Dr. Wheatley and most coauthors had no relevant disclosures. One coauthor received grants and fees from Medtronic for another similar study. Dr. Rodriguez-Oroz reported relationships with Medtronic and several companies that manufacture dopaminergic agents.

Parkinson's disease patients report better quality of life after 1 year of deep brain stimulation than with best medical therapy, according to the largest randomized trial of the two treatment options for patients with advanced disease.

In the PD SURG trial, deep brain stimulation (DBS) resulted in greater improvement in motor function scores and complications of therapy, as well as lower use of dopaminergic drugs, than did best medical therapy. However, both arms of the open-label study experienced a similar amount of cognitive decline, with significantly poorer function in verbal fluency and vocabulary in DBS patients.

The trial largely corroborates the results observed in two previous trials of DBS vs. best medical therapy that recorded follow-up out to 6 months (N. Engl. J. Med. 2006;355:896–908; JAMA 2009;301:63–73).

“Surgery is likely to remain an important treatment option for patients with PD, especially if the way in which deep brain stimulation exerts its therapeutic benefits is better understood, if its use can be optimised by better electrode placement and settings, and if patients who would have the greatest benefit can be better identified,” Dr. Keith Wheatley of the University of Birmingham (England) and his colleagues concluded (Lancet Neurol. 2010 April 29 [doi:10.1016/S1474-4422(10)70093-4

During 2000-2006, Dr. Wheatley and his associates randomized 366 patients evenly to either treatment group at 13 neurosurgical centers in the United Kingdom. The patients had a mean age of 59 years and were mostly men (about 70%) with a mean disease duration of 11.4 years. In each group, 45 patients were taking apomorphine at study entry; 145 total were taking it before the study.

Of 178 patients who underwent surgery, DBS targeted the subthalamic nucleus in 174 and the globus pallidus pars interna in 4. All but two of the surgeries were bilateral. A total of 12 patients in the best medical therapy arm underwent DBS surgery between baseline and 1 year but were analyzed in the medical therapy arm anyway.

Measurement of quality of life with the Parkinson's Disease Questionnaire (PDQ-39) after 1 year—the primary outcome—improved significantly more in DBS patients than in medical therapy patients (−5.0 vs. −0.3).

During “on” periods, the mean United Parkinson's Disease Rating Scale (UPDRS) total score after 1 year improved by a mean of 6.6 points in the surgery group and worsened by 1.6 points in the medical therapy group, which was a significant difference. In “off” time, UPDRS scores improved significantly more in DBS patients (−27.4) than in medical therapy patients (−0.9 points).

Cognitive status measured with the Dementia Rating Scale-II (DRS-II) declined by 0.4 points in each group after 1 year. Neuropsychological testing in a subset of patients revealed that verbal fluency and vocabulary had declined after 1 year significantly more in patients who had undergone surgery than in patients who took medication alone.

Treatment with DBS also resulted in a significantly lower mean levodopa equivalent dose after 1 year than did medical therapy alone (894 vs. 1,347 mg/day).

“The cost of surgery will be partly offset by the reduction in the amount of drug therapy required by patients who have had surgery. In particular, if apomorphine or continuous intestinal infusions of levodopa, with high recurrent costs, are the alternative drug treatment options, the cost-effectiveness equation might favor surgery … thus, it is important to identify patients who are or are not likely to benefit from surgery when the risks and costs are taken into account,” they wrote.

Overall, 36 surgery patients experienced 43 serious adverse events, including 16 infections. In the surgery group, 25 Parkinson's disease–related and drug-related serious adverse events occurred in 20 patients, compared with 14 events in 13 medical therapy patients. The two remaining serious adverse events in the group included one unsuccessful postoperative suicide and one death from hemorrhage during surgery.

The trial has a number of strengths that improved on previous trials, including a larger number of patients, a longer follow-up, and treatment with continuous infusions of apomorphine, Dr. Maria C. Rodriguez-Oroz wrote in an editorial (Lancet Neurol. 2010 April 29 [doi:10.1016/S1474-4422(10)70108-3

Dr. Rodriguez-Oroz of the Clinica Universidad de Navarra, Pamplona, Spain, added that some limitations of the trial raise questions about the results. For example, neither patients nor evaluators were masked to treatment. Evaluations of dyskinesia and “off” period time could have been done with a more reliable tool than the complications of therapy subsection of the UPDRS. Investigators made their own judgment about whether a patient was in the “on” state (without assessment of inter-rater reliability). The DRS-II might be inadequate to assess cognitive ability in Parkinson's. And the investigators did not record nonserious adverse events.

Major Finding: Measurement of quality of life with the PDQ-39 after 1 year improved significantly more in DBS patients than in medical therapy patients (−5.0 vs. −0.3).

Data Source: A randomized, open-label trial of 366 patients with Parkinson's disease.

Disclosures: Trial was funded by the U.K. Medical Research Council, Parkinson's U.K., and the U.K. Department of Health. Dr. Wheatley and most coauthors had no relevant disclosures. One coauthor received grants and fees from Medtronic for another similar study. Dr. Rodriguez-Oroz reported relationships with Medtronic and several companies that manufacture dopaminergic agents.

Parkinson's disease patients report better quality of life after 1 year of deep brain stimulation than with best medical therapy, according to the largest randomized trial of the two treatment options for patients with advanced disease.

In the PD SURG trial, deep brain stimulation (DBS) resulted in greater improvement in motor function scores and complications of therapy, as well as lower use of dopaminergic drugs, than did best medical therapy. However, both arms of the open-label study experienced a similar amount of cognitive decline, with significantly poorer function in verbal fluency and vocabulary in DBS patients.

The trial largely corroborates the results observed in two previous trials of DBS vs. best medical therapy that recorded follow-up out to 6 months (N. Engl. J. Med. 2006;355:896–908; JAMA 2009;301:63–73).

“Surgery is likely to remain an important treatment option for patients with PD, especially if the way in which deep brain stimulation exerts its therapeutic benefits is better understood, if its use can be optimised by better electrode placement and settings, and if patients who would have the greatest benefit can be better identified,” Dr. Keith Wheatley of the University of Birmingham (England) and his colleagues concluded (Lancet Neurol. 2010 April 29 [doi:10.1016/S1474-4422(10)70093-4

During 2000-2006, Dr. Wheatley and his associates randomized 366 patients evenly to either treatment group at 13 neurosurgical centers in the United Kingdom. The patients had a mean age of 59 years and were mostly men (about 70%) with a mean disease duration of 11.4 years. In each group, 45 patients were taking apomorphine at study entry; 145 total were taking it before the study.

Of 178 patients who underwent surgery, DBS targeted the subthalamic nucleus in 174 and the globus pallidus pars interna in 4. All but two of the surgeries were bilateral. A total of 12 patients in the best medical therapy arm underwent DBS surgery between baseline and 1 year but were analyzed in the medical therapy arm anyway.

Measurement of quality of life with the Parkinson's Disease Questionnaire (PDQ-39) after 1 year—the primary outcome—improved significantly more in DBS patients than in medical therapy patients (−5.0 vs. −0.3).

During “on” periods, the mean United Parkinson's Disease Rating Scale (UPDRS) total score after 1 year improved by a mean of 6.6 points in the surgery group and worsened by 1.6 points in the medical therapy group, which was a significant difference. In “off” time, UPDRS scores improved significantly more in DBS patients (−27.4) than in medical therapy patients (−0.9 points).

Cognitive status measured with the Dementia Rating Scale-II (DRS-II) declined by 0.4 points in each group after 1 year. Neuropsychological testing in a subset of patients revealed that verbal fluency and vocabulary had declined after 1 year significantly more in patients who had undergone surgery than in patients who took medication alone.

Treatment with DBS also resulted in a significantly lower mean levodopa equivalent dose after 1 year than did medical therapy alone (894 vs. 1,347 mg/day).

“The cost of surgery will be partly offset by the reduction in the amount of drug therapy required by patients who have had surgery. In particular, if apomorphine or continuous intestinal infusions of levodopa, with high recurrent costs, are the alternative drug treatment options, the cost-effectiveness equation might favor surgery … thus, it is important to identify patients who are or are not likely to benefit from surgery when the risks and costs are taken into account,” they wrote.

Overall, 36 surgery patients experienced 43 serious adverse events, including 16 infections. In the surgery group, 25 Parkinson's disease–related and drug-related serious adverse events occurred in 20 patients, compared with 14 events in 13 medical therapy patients. The two remaining serious adverse events in the group included one unsuccessful postoperative suicide and one death from hemorrhage during surgery.

The trial has a number of strengths that improved on previous trials, including a larger number of patients, a longer follow-up, and treatment with continuous infusions of apomorphine, Dr. Maria C. Rodriguez-Oroz wrote in an editorial (Lancet Neurol. 2010 April 29 [doi:10.1016/S1474-4422(10)70108-3

Dr. Rodriguez-Oroz of the Clinica Universidad de Navarra, Pamplona, Spain, added that some limitations of the trial raise questions about the results. For example, neither patients nor evaluators were masked to treatment. Evaluations of dyskinesia and “off” period time could have been done with a more reliable tool than the complications of therapy subsection of the UPDRS. Investigators made their own judgment about whether a patient was in the “on” state (without assessment of inter-rater reliability). The DRS-II might be inadequate to assess cognitive ability in Parkinson's. And the investigators did not record nonserious adverse events.

Major Finding: Scores on the motor subscale of the UPDRS improved from baseline by similar amounts after 2 years of DBS targeting the globus pallidus interna (from 42 to 30) or subthalamic nucleus (from 43 to about 32.5).

Data Source: Randomized, rater-blinded trial of 299 patients with idiopathic Parkinson's disease.

Disclosures: The Department of Veterans Affairs, the National Institute of Neurological Disorders and Stroke, and Medtronic, maker of a DBS device, funded the trial. Dr. Follett had no relevant financial disclosures to report.

TORONTO — Motor function in Parkinson's disease patients improved by a similar amount after 2 years of bilateral deep brain stimulation of the subthalamic nucleus or globus pallidus in the first blinded, randomized trial to compare outcomes with the two targets.

This result may free clinicians to give greater weight to the effects of deep brain stimulation (DBS) at each site on quality of life, neuropsychiatric symptoms, and medication reduction, Dr. Kenneth A. Follett said at the annual meeting of the American Academy of Neurology.

The subthalamic nucleus (STN) has become the preferred and most common target of deep brain stimulation for Parkinson's disease patients, even though “there really is a lack of high-quality evidence that STN-DBS provides clinical outcomes that are superior to outcomes with GPi [globus pallidus interna]–DBS,” said Dr. Follett, professor and chief of neurosurgery at the University of Nebraska Medical Center, Omaha.

GPi-targeted patients completed the trial with slightly better neurocognitive performance in some areas and slightly more “on” stimulation time, but also with significantly greater medication use, compared with STN-targeted patients.

“The bottom line is that given the uniformity of outcomes, clinicians may comfortably take into consideration factors other than just motor function when selecting a target. For example, you may have preferences based on what you perceive is in need of targeting one site or another, the ease of programming one site or another.

“You may decide it's prudent to select one target versus the other based on symptoms. For example, a patient with severe, dose-limiting dyskinesias may be a [slightly] better candidate for GPi. A patient who has medication side effects such as nausea or hallucinations at a low dose may be a better candidate for STN-DBS, knowing that she'll be more likely to reduce medications postoperatively,” Dr. Follett said.

Although it is unclear whether medication reduction is necessarily desirable for all patients, it “may play some role ultimately in selection of target,” he noted.

During 2002–2008, patients enrolled in the trial and underwent follow-up at 13 VA Parkinson's Disease Research, Education, and Clinical Care Centers and their affiliated universities, Dr. Follett said.

To be enrolled, patients had to be at least moderately disabled off medications (Hoehn and Yahr stage 2 or worse) and be l-dopa responsive with clearly defined “on” periods, and to have a diagnosis of idiopathic Parkinson's disease, persistent disabling symptoms such as dyskinesias, motor fluctuations, and a minimum of 3 hours per day in the “off” state or “on” with dyskinesias.

The investigators excluded patients with “Parkinson's Plus” or secondary or atypical Parkinson's syndromes, previous surgeries for Parkinson's disease, medical contraindications to surgery or stimulation, contraindications to MRI, active alcohol or substance abuse, or a Mini-Mental Status Examination score of 24 or lower or other neuropsychological dysfunction.

The randomized DBS trial was embedded within another randomized trial that compared best medical therapy (BMT) with pooled outcomes of DBS. After 6 months, clinical outcomes were examined and BMT patients were randomized to either DBS target.

In an interim analysis of the data when 134 patients had been randomized to BMT and 121 to DBS, the data safety monitoring board decided to stop randomizing patients to BMT because enough data had been gathered to compare the primary outcome.

An additional 61 patients were randomized to only one of the DBS targets, leaving a total of 316 enrolled patients. The investigators conducted follow-up with the patients for 2 years after DBS implantation, meaning that patients who had been initially randomized to BMT received 30 months of follow-up.

A total of 17 BMT patients withdrew from the trial without being randomized to DBS, leaving 152 patients in the GPi group and 147 in the STN group. These patients had a mean age of about 62 years and had been on Parkinson's disease medications for a mean of 11–12 years. Patients and the clinical raters were blinded to the target brain region.

In the “on stimulation, off medication state,” scores on the motor subscale (part III) of the United Parkinson's Disease Rating Scale (UPDRS III) at 6 months improved similarly in the GPi (from 42 at baseline to 30) and STN patients (from 43 at baseline to about 32.5). The scores at 2 years—the primary outcome of the trial—were no different. Additional longitudinal analyses with mixed-effect models that used worst-case scenarios for all incomplete data also found no difference between the groups.

“Regardless of how we looked at the data, the result was the same,” he said. “This was a very robust finding.”

These 25%–30% reductions in UPDRS III scores are not as great as the 40%–50% improvements that have been reported in open-label, uncontrolled studies. This might be a result of having slightly fewer disabled patients in the current study than in studies described in earlier reports, which included patients with UPDRS III scores in the high 40s and low 50s, Dr. Follett said. He noted the possibility of a “floor effect” to DBS, meaning that “you can only improve patients to a certain point, so the lower the UPDRS starting score, the [lower the percentage of] improvement there's going to be.”

Data from the patients' motor diaries indicated that at 2 years, GPi patients had about 1 hour more of “on” stimulation time without dyskinesias (from 6.5 to 11.4 hours) than did STN patients (from 7 to 11 hours), although this was not statistically significant.

Quality of life assessments at baseline with the Parkinson's Disease Questionnaire (PDQ-39) indicated that STN-targeted patients had slightly worse scores for emotional well-being, social support, and cognition. Dr. Follett suggested that these “very small point differences” might reflect the fact that the STN arm of the trial included slightly fewer men than women, who “tend to report slightly greater disability in chronic disease compared with men.”

At 2 years, there were no differences between the groups on the PDQ-39. With the exception of social support and communication, quality of life improved on each subscale of the PDQ-39. GPi patients reported slightly improved depressive symptoms on the Beck Depression Inventory, compared with slight worsening of symptoms in STN patients. But the difference was not statistically significant.

Baseline assessments of neurocognitive function and mood in category fluency and learning and memory also were slightly worse in STN patients than in GPi patients. After 2 years of DBS, neurocognitive function worsened slightly in both groups. STN patients experienced significantly greater worsening of visuomotor processing speed than did GPi patients, although the change was slight.

No differences between the groups were detected on other UPDRS subscales (I, II, and IV).

Because the trial was not powered to test for differences between secondary outcomes, Dr. Follett noted that further analyses of the data will contend with what to make of very small differences that are detected between groups because of the large sample size.

“The question we need to address is, 'Are those small differences that might be statistically significant [also] clinically significant?' So keep in mind that some of these statistically significant differences are fairly small in terms of points and might not be clinically significant.”

Use of Parkinson's disease medications declined by a significantly greater percentage with STN-DBS (30% decrease) than with GPi-DBS (about a 20% decrease).

Similar numbers of serious adverse events occurred in the GPi (77) and STN (83) arms, and there was no difference in the type of events that were seen, such as prolonged or new hospitalization, repeat surgery, morbidity, or death.

“What's going to be much more important is how these folks do 5 years out, 8 years out, 10 years out. Is there a point at which Parkinson's disease progresses or the beneficial effect of DBS will be lost?” he asked.

My Take

Nonmotor Effects Rise in Importance

STN has been the most common target of DBS for Parkinson's disease ever since deep brain stimulation pioneer Dr. Alim-Louis Benabid of France suggested in the mid-1990s that it was a better target for DBS than the GPi. Given the similar degree of motor improvement observed with either target in this trial, the choice of stimulation site could now depend on the presence of other factors, such as dyskinesia. (Most clinicians would say that the GPi is a better target than the STN for dyskinesia.)

It will be important to follow up with the patients as planned, but previous reports of DBS with longer than 2 years of follow-up seem to indicate that the effect of stimulation does not decline substantially beyond that. However, there are few reports of more than 5 years of follow-up.

Because the trial was designed nearly 10 years ago, the investigators might not be able to analyze their results for some of the issues that have arisen more recently in Parkinson's disease research, such as the dopamine dysregulation syndrome (including pathological gambling and impulsivity).

It will be important to resolve whether the greater level of depressive symptoms observed in the STN patients is a reflection of their greater reduction in medication use or is a potential effect of stimulating that site. If reducing medications increases depressive symptoms in STN patients, then it could be a reason to not reduce medication use.

MARK HALLETT, M.D., is the chief of the Medical Neurology Branch of the National Institute of Neurological Disorders and Stroke, Bethesda, Md. He has no relevant disclosures.

Vitals

Major Finding: Scores on the motor subscale of the UPDRS improved from baseline by similar amounts after 2 years of DBS targeting the globus pallidus interna (from 42 to 30) or subthalamic nucleus (from 43 to about 32.5).

Data Source: Randomized, rater-blinded trial of 299 patients with idiopathic Parkinson's disease.

Disclosures: The Department of Veterans Affairs, the National Institute of Neurological Disorders and Stroke, and Medtronic, maker of a DBS device, funded the trial. Dr. Follett had no relevant financial disclosures to report.

TORONTO — Motor function in Parkinson's disease patients improved by a similar amount after 2 years of bilateral deep brain stimulation of the subthalamic nucleus or globus pallidus in the first blinded, randomized trial to compare outcomes with the two targets.

This result may free clinicians to give greater weight to the effects of deep brain stimulation (DBS) at each site on quality of life, neuropsychiatric symptoms, and medication reduction, Dr. Kenneth A. Follett said at the annual meeting of the American Academy of Neurology.

The subthalamic nucleus (STN) has become the preferred and most common target of deep brain stimulation for Parkinson's disease patients, even though “there really is a lack of high-quality evidence that STN-DBS provides clinical outcomes that are superior to outcomes with GPi [globus pallidus interna]–DBS,” said Dr. Follett, professor and chief of neurosurgery at the University of Nebraska Medical Center, Omaha.

GPi-targeted patients completed the trial with slightly better neurocognitive performance in some areas and slightly more “on” stimulation time, but also with significantly greater medication use, compared with STN-targeted patients.

“The bottom line is that given the uniformity of outcomes, clinicians may comfortably take into consideration factors other than just motor function when selecting a target. For example, you may have preferences based on what you perceive is in need of targeting one site or another, the ease of programming one site or another.

“You may decide it's prudent to select one target versus the other based on symptoms. For example, a patient with severe, dose-limiting dyskinesias may be a [slightly] better candidate for GPi. A patient who has medication side effects such as nausea or hallucinations at a low dose may be a better candidate for STN-DBS, knowing that she'll be more likely to reduce medications postoperatively,” Dr. Follett said.

Although it is unclear whether medication reduction is necessarily desirable for all patients, it “may play some role ultimately in selection of target,” he noted.

During 2002–2008, patients enrolled in the trial and underwent follow-up at 13 VA Parkinson's Disease Research, Education, and Clinical Care Centers and their affiliated universities, Dr. Follett said.

To be enrolled, patients had to be at least moderately disabled off medications (Hoehn and Yahr stage 2 or worse) and be l-dopa responsive with clearly defined “on” periods, and to have a diagnosis of idiopathic Parkinson's disease, persistent disabling symptoms such as dyskinesias, motor fluctuations, and a minimum of 3 hours per day in the “off” state or “on” with dyskinesias.

The investigators excluded patients with “Parkinson's Plus” or secondary or atypical Parkinson's syndromes, previous surgeries for Parkinson's disease, medical contraindications to surgery or stimulation, contraindications to MRI, active alcohol or substance abuse, or a Mini-Mental Status Examination score of 24 or lower or other neuropsychological dysfunction.

The randomized DBS trial was embedded within another randomized trial that compared best medical therapy (BMT) with pooled outcomes of DBS. After 6 months, clinical outcomes were examined and BMT patients were randomized to either DBS target.

In an interim analysis of the data when 134 patients had been randomized to BMT and 121 to DBS, the data safety monitoring board decided to stop randomizing patients to BMT because enough data had been gathered to compare the primary outcome.

An additional 61 patients were randomized to only one of the DBS targets, leaving a total of 316 enrolled patients. The investigators conducted follow-up with the patients for 2 years after DBS implantation, meaning that patients who had been initially randomized to BMT received 30 months of follow-up.

A total of 17 BMT patients withdrew from the trial without being randomized to DBS, leaving 152 patients in the GPi group and 147 in the STN group. These patients had a mean age of about 62 years and had been on Parkinson's disease medications for a mean of 11–12 years. Patients and the clinical raters were blinded to the target brain region.

In the “on stimulation, off medication state,” scores on the motor subscale (part III) of the United Parkinson's Disease Rating Scale (UPDRS III) at 6 months improved similarly in the GPi (from 42 at baseline to 30) and STN patients (from 43 at baseline to about 32.5). The scores at 2 years—the primary outcome of the trial—were no different. Additional longitudinal analyses with mixed-effect models that used worst-case scenarios for all incomplete data also found no difference between the groups.

“Regardless of how we looked at the data, the result was the same,” he said. “This was a very robust finding.”

These 25%–30% reductions in UPDRS III scores are not as great as the 40%–50% improvements that have been reported in open-label, uncontrolled studies. This might be a result of having slightly fewer disabled patients in the current study than in studies described in earlier reports, which included patients with UPDRS III scores in the high 40s and low 50s, Dr. Follett said. He noted the possibility of a “floor effect” to DBS, meaning that “you can only improve patients to a certain point, so the lower the UPDRS starting score, the [lower the percentage of] improvement there's going to be.”

Data from the patients' motor diaries indicated that at 2 years, GPi patients had about 1 hour more of “on” stimulation time without dyskinesias (from 6.5 to 11.4 hours) than did STN patients (from 7 to 11 hours), although this was not statistically significant.

Quality of life assessments at baseline with the Parkinson's Disease Questionnaire (PDQ-39) indicated that STN-targeted patients had slightly worse scores for emotional well-being, social support, and cognition. Dr. Follett suggested that these “very small point differences” might reflect the fact that the STN arm of the trial included slightly fewer men than women, who “tend to report slightly greater disability in chronic disease compared with men.”

At 2 years, there were no differences between the groups on the PDQ-39. With the exception of social support and communication, quality of life improved on each subscale of the PDQ-39. GPi patients reported slightly improved depressive symptoms on the Beck Depression Inventory, compared with slight worsening of symptoms in STN patients. But the difference was not statistically significant.

Baseline assessments of neurocognitive function and mood in category fluency and learning and memory also were slightly worse in STN patients than in GPi patients. After 2 years of DBS, neurocognitive function worsened slightly in both groups. STN patients experienced significantly greater worsening of visuomotor processing speed than did GPi patients, although the change was slight.

No differences between the groups were detected on other UPDRS subscales (I, II, and IV).

Because the trial was not powered to test for differences between secondary outcomes, Dr. Follett noted that further analyses of the data will contend with what to make of very small differences that are detected between groups because of the large sample size.

“The question we need to address is, 'Are those small differences that might be statistically significant [also] clinically significant?' So keep in mind that some of these statistically significant differences are fairly small in terms of points and might not be clinically significant.”

Use of Parkinson's disease medications declined by a significantly greater percentage with STN-DBS (30% decrease) than with GPi-DBS (about a 20% decrease).

Similar numbers of serious adverse events occurred in the GPi (77) and STN (83) arms, and there was no difference in the type of events that were seen, such as prolonged or new hospitalization, repeat surgery, morbidity, or death.

“What's going to be much more important is how these folks do 5 years out, 8 years out, 10 years out. Is there a point at which Parkinson's disease progresses or the beneficial effect of DBS will be lost?” he asked.

My Take

Nonmotor Effects Rise in Importance

STN has been the most common target of DBS for Parkinson's disease ever since deep brain stimulation pioneer Dr. Alim-Louis Benabid of France suggested in the mid-1990s that it was a better target for DBS than the GPi. Given the similar degree of motor improvement observed with either target in this trial, the choice of stimulation site could now depend on the presence of other factors, such as dyskinesia. (Most clinicians would say that the GPi is a better target than the STN for dyskinesia.)

It will be important to follow up with the patients as planned, but previous reports of DBS with longer than 2 years of follow-up seem to indicate that the effect of stimulation does not decline substantially beyond that. However, there are few reports of more than 5 years of follow-up.

Because the trial was designed nearly 10 years ago, the investigators might not be able to analyze their results for some of the issues that have arisen more recently in Parkinson's disease research, such as the dopamine dysregulation syndrome (including pathological gambling and impulsivity).

It will be important to resolve whether the greater level of depressive symptoms observed in the STN patients is a reflection of their greater reduction in medication use or is a potential effect of stimulating that site. If reducing medications increases depressive symptoms in STN patients, then it could be a reason to not reduce medication use.

MARK HALLETT, M.D., is the chief of the Medical Neurology Branch of the National Institute of Neurological Disorders and Stroke, Bethesda, Md. He has no relevant disclosures.

Vitals

Major Finding: Scores on the motor subscale of the UPDRS improved from baseline by similar amounts after 2 years of DBS targeting the globus pallidus interna (from 42 to 30) or subthalamic nucleus (from 43 to about 32.5).

Data Source: Randomized, rater-blinded trial of 299 patients with idiopathic Parkinson's disease.

Disclosures: The Department of Veterans Affairs, the National Institute of Neurological Disorders and Stroke, and Medtronic, maker of a DBS device, funded the trial. Dr. Follett had no relevant financial disclosures to report.

TORONTO — Motor function in Parkinson's disease patients improved by a similar amount after 2 years of bilateral deep brain stimulation of the subthalamic nucleus or globus pallidus in the first blinded, randomized trial to compare outcomes with the two targets.

This result may free clinicians to give greater weight to the effects of deep brain stimulation (DBS) at each site on quality of life, neuropsychiatric symptoms, and medication reduction, Dr. Kenneth A. Follett said at the annual meeting of the American Academy of Neurology.

The subthalamic nucleus (STN) has become the preferred and most common target of deep brain stimulation for Parkinson's disease patients, even though “there really is a lack of high-quality evidence that STN-DBS provides clinical outcomes that are superior to outcomes with GPi [globus pallidus interna]–DBS,” said Dr. Follett, professor and chief of neurosurgery at the University of Nebraska Medical Center, Omaha.

GPi-targeted patients completed the trial with slightly better neurocognitive performance in some areas and slightly more “on” stimulation time, but also with significantly greater medication use, compared with STN-targeted patients.

“The bottom line is that given the uniformity of outcomes, clinicians may comfortably take into consideration factors other than just motor function when selecting a target. For example, you may have preferences based on what you perceive is in need of targeting one site or another, the ease of programming one site or another.

“You may decide it's prudent to select one target versus the other based on symptoms. For example, a patient with severe, dose-limiting dyskinesias may be a [slightly] better candidate for GPi. A patient who has medication side effects such as nausea or hallucinations at a low dose may be a better candidate for STN-DBS, knowing that she'll be more likely to reduce medications postoperatively,” Dr. Follett said.

Although it is unclear whether medication reduction is necessarily desirable for all patients, it “may play some role ultimately in selection of target,” he noted.

During 2002–2008, patients enrolled in the trial and underwent follow-up at 13 VA Parkinson's Disease Research, Education, and Clinical Care Centers and their affiliated universities, Dr. Follett said.

To be enrolled, patients had to be at least moderately disabled off medications (Hoehn and Yahr stage 2 or worse) and be l-dopa responsive with clearly defined “on” periods, and to have a diagnosis of idiopathic Parkinson's disease, persistent disabling symptoms such as dyskinesias, motor fluctuations, and a minimum of 3 hours per day in the “off” state or “on” with dyskinesias.

The investigators excluded patients with “Parkinson's Plus” or secondary or atypical Parkinson's syndromes, previous surgeries for Parkinson's disease, medical contraindications to surgery or stimulation, contraindications to MRI, active alcohol or substance abuse, or a Mini-Mental Status Examination score of 24 or lower or other neuropsychological dysfunction.

The randomized DBS trial was embedded within another randomized trial that compared best medical therapy (BMT) with pooled outcomes of DBS. After 6 months, clinical outcomes were examined and BMT patients were randomized to either DBS target.

In an interim analysis of the data when 134 patients had been randomized to BMT and 121 to DBS, the data safety monitoring board decided to stop randomizing patients to BMT because enough data had been gathered to compare the primary outcome.

An additional 61 patients were randomized to only one of the DBS targets, leaving a total of 316 enrolled patients. The investigators conducted follow-up with the patients for 2 years after DBS implantation, meaning that patients who had been initially randomized to BMT received 30 months of follow-up.

A total of 17 BMT patients withdrew from the trial without being randomized to DBS, leaving 152 patients in the GPi group and 147 in the STN group. These patients had a mean age of about 62 years and had been on Parkinson's disease medications for a mean of 11–12 years. Patients and the clinical raters were blinded to the target brain region.

In the “on stimulation, off medication state,” scores on the motor subscale (part III) of the United Parkinson's Disease Rating Scale (UPDRS III) at 6 months improved similarly in the GPi (from 42 at baseline to 30) and STN patients (from 43 at baseline to about 32.5). The scores at 2 years—the primary outcome of the trial—were no different. Additional longitudinal analyses with mixed-effect models that used worst-case scenarios for all incomplete data also found no difference between the groups.

“Regardless of how we looked at the data, the result was the same,” he said. “This was a very robust finding.”

These 25%–30% reductions in UPDRS III scores are not as great as the 40%–50% improvements that have been reported in open-label, uncontrolled studies. This might be a result of having slightly fewer disabled patients in the current study than in studies described in earlier reports, which included patients with UPDRS III scores in the high 40s and low 50s, Dr. Follett said. He noted the possibility of a “floor effect” to DBS, meaning that “you can only improve patients to a certain point, so the lower the UPDRS starting score, the [lower the percentage of] improvement there's going to be.”

Data from the patients' motor diaries indicated that at 2 years, GPi patients had about 1 hour more of “on” stimulation time without dyskinesias (from 6.5 to 11.4 hours) than did STN patients (from 7 to 11 hours), although this was not statistically significant.

Quality of life assessments at baseline with the Parkinson's Disease Questionnaire (PDQ-39) indicated that STN-targeted patients had slightly worse scores for emotional well-being, social support, and cognition. Dr. Follett suggested that these “very small point differences” might reflect the fact that the STN arm of the trial included slightly fewer men than women, who “tend to report slightly greater disability in chronic disease compared with men.”

At 2 years, there were no differences between the groups on the PDQ-39. With the exception of social support and communication, quality of life improved on each subscale of the PDQ-39. GPi patients reported slightly improved depressive symptoms on the Beck Depression Inventory, compared with slight worsening of symptoms in STN patients. But the difference was not statistically significant.

Baseline assessments of neurocognitive function and mood in category fluency and learning and memory also were slightly worse in STN patients than in GPi patients. After 2 years of DBS, neurocognitive function worsened slightly in both groups. STN patients experienced significantly greater worsening of visuomotor processing speed than did GPi patients, although the change was slight.

No differences between the groups were detected on other UPDRS subscales (I, II, and IV).

Because the trial was not powered to test for differences between secondary outcomes, Dr. Follett noted that further analyses of the data will contend with what to make of very small differences that are detected between groups because of the large sample size.

“The question we need to address is, 'Are those small differences that might be statistically significant [also] clinically significant?' So keep in mind that some of these statistically significant differences are fairly small in terms of points and might not be clinically significant.”

Use of Parkinson's disease medications declined by a significantly greater percentage with STN-DBS (30% decrease) than with GPi-DBS (about a 20% decrease).

Similar numbers of serious adverse events occurred in the GPi (77) and STN (83) arms, and there was no difference in the type of events that were seen, such as prolonged or new hospitalization, repeat surgery, morbidity, or death.

“What's going to be much more important is how these folks do 5 years out, 8 years out, 10 years out. Is there a point at which Parkinson's disease progresses or the beneficial effect of DBS will be lost?” he asked.

My Take

Nonmotor Effects Rise in Importance

STN has been the most common target of DBS for Parkinson's disease ever since deep brain stimulation pioneer Dr. Alim-Louis Benabid of France suggested in the mid-1990s that it was a better target for DBS than the GPi. Given the similar degree of motor improvement observed with either target in this trial, the choice of stimulation site could now depend on the presence of other factors, such as dyskinesia. (Most clinicians would say that the GPi is a better target than the STN for dyskinesia.)

It will be important to follow up with the patients as planned, but previous reports of DBS with longer than 2 years of follow-up seem to indicate that the effect of stimulation does not decline substantially beyond that. However, there are few reports of more than 5 years of follow-up.

Because the trial was designed nearly 10 years ago, the investigators might not be able to analyze their results for some of the issues that have arisen more recently in Parkinson's disease research, such as the dopamine dysregulation syndrome (including pathological gambling and impulsivity).

It will be important to resolve whether the greater level of depressive symptoms observed in the STN patients is a reflection of their greater reduction in medication use or is a potential effect of stimulating that site. If reducing medications increases depressive symptoms in STN patients, then it could be a reason to not reduce medication use.

MARK HALLETT, M.D., is the chief of the Medical Neurology Branch of the National Institute of Neurological Disorders and Stroke, Bethesda, Md. He has no relevant disclosures.

Vitals

Major Finding: Treatment with a range of doses of IVIG for 18 months resulted in a mean increase of 6.7% in lateral ventricular volume, which was significantly lower than the 12.3% increase observed with placebo.

Data Source: A double-blind, placebo-controlled, randomized phase II trial of 24 patients with mild-to-moderate Alzheimer's disease.

Disclosures: Baxter Healthcare, which produces Gammagard, the IVIG product used by the investigators, sponsored the study, with additional support from the Citigroup Foundation and the National Institutes of Health. Dr. Relkin reported receiving a research grant from Baxter Healthcare.

TORONTO — Intravenous immunoglobulin therapy reduced brain atrophy in patients with mild to moderate Alzheimer's disease in a small phase II trial. The finding suggests that specific IgG antibody components found in the blood product might be treatment candidates for the disease.

“Relative to what we have available right now [to treat Alzheimer's], this is a very promising outcome, and it's associated with a reduction in the rate of brain atrophy comparable to age-matched normals,” Dr. Norman Relkin said during a poster presentation at the annual meeting of the American Academy of Neurology. Enlargement of the cerebral lateral ventricles is known to occur as a consequence of brain atrophy in AD. This increase in ventricular volume is correlated with cognitive decline and increases in Alzheimer's disease neuropathology.

Dr. Relkin, who is the director of the Memory Disorders Program at New York-Presbyterian Hospital/Weill Cornell Medical Center, and his colleagues compared intravenous immunoglobulin (IVIG) therapy against placebo in a 6-month, double-blind, randomized study of 24 patients with mild to moderate AD.

In a 12-month extension phase of the study, 16 patients who originally were randomized to IVIG continued to receive the same doses of IVIG, whereas 8 placebo-treated patients were re-randomized to one of four doses of IVIG.

IVIG exhibited a dose-dependent effect on brain atrophy in which higher doses resulted in less atrophy. Among 14 IVIG-treated patients who underwent volumetric MRI at baseline and after 18 months, the yearly increase in lateral ventricle volume measured with volumetric MRI was lowest in patients treated with 0.4 mg/kg every 2 weeks (2.4%) and highest in those treated with 0.2 mg/kg every 2 weeks (11.2%).

The doses of IVIG that were given to patients ranged from 0.2 mg/kg every 2 weeks to 0.8 mg/kg every 4 weeks.

The volume of the lateral ventricles increased by a mean of 6.7% per year during treatment with IVIG (all doses combined), which was significantly lower than the 12.3% annual rate of increase observed in six placebo-treated patients.

The reduction in brain atrophy was significantly correlated with improvement in clinical outcomes at 18 months on the Clinical Global Impression of Change and the cognitive subscale of the Alzheimer's Disease Assessment Scale. Baseline characteristics of the patients were not correlated with volumetric MRI outcomes.

“We are not encouraging people to use [IVIG] off-label for Alzheimer's disease, even though it has been safe and well tolerated in these small studies,” Dr. Relkin said in an interview. “It has never been studied in the Alzheimer's population before.”

“This is a 'kitchen sink' approach, so the next step is to find what is in [IVIG] that is causing the therapeutic effect.…We know that it has a fairly good complement of antiamyloid antibodies. Those are prime candidates, but we don't know for sure yet that those are the ones responsible for a therapeutic effect,” he said.

The ventricular enlargement rate was greater with placebo (left) than with IVIG (right).

Source Courtesy Dr. Dana Moore and Dr. Norman Relkin

Major Finding: Treatment with a range of doses of IVIG for 18 months resulted in a mean increase of 6.7% in lateral ventricular volume, which was significantly lower than the 12.3% increase observed with placebo.

Data Source: A double-blind, placebo-controlled, randomized phase II trial of 24 patients with mild-to-moderate Alzheimer's disease.

Disclosures: Baxter Healthcare, which produces Gammagard, the IVIG product used by the investigators, sponsored the study, with additional support from the Citigroup Foundation and the National Institutes of Health. Dr. Relkin reported receiving a research grant from Baxter Healthcare.

TORONTO — Intravenous immunoglobulin therapy reduced brain atrophy in patients with mild to moderate Alzheimer's disease in a small phase II trial. The finding suggests that specific IgG antibody components found in the blood product might be treatment candidates for the disease.

“Relative to what we have available right now [to treat Alzheimer's], this is a very promising outcome, and it's associated with a reduction in the rate of brain atrophy comparable to age-matched normals,” Dr. Norman Relkin said during a poster presentation at the annual meeting of the American Academy of Neurology. Enlargement of the cerebral lateral ventricles is known to occur as a consequence of brain atrophy in AD. This increase in ventricular volume is correlated with cognitive decline and increases in Alzheimer's disease neuropathology.

Dr. Relkin, who is the director of the Memory Disorders Program at New York-Presbyterian Hospital/Weill Cornell Medical Center, and his colleagues compared intravenous immunoglobulin (IVIG) therapy against placebo in a 6-month, double-blind, randomized study of 24 patients with mild to moderate AD.

In a 12-month extension phase of the study, 16 patients who originally were randomized to IVIG continued to receive the same doses of IVIG, whereas 8 placebo-treated patients were re-randomized to one of four doses of IVIG.

IVIG exhibited a dose-dependent effect on brain atrophy in which higher doses resulted in less atrophy. Among 14 IVIG-treated patients who underwent volumetric MRI at baseline and after 18 months, the yearly increase in lateral ventricle volume measured with volumetric MRI was lowest in patients treated with 0.4 mg/kg every 2 weeks (2.4%) and highest in those treated with 0.2 mg/kg every 2 weeks (11.2%).

The doses of IVIG that were given to patients ranged from 0.2 mg/kg every 2 weeks to 0.8 mg/kg every 4 weeks.

The volume of the lateral ventricles increased by a mean of 6.7% per year during treatment with IVIG (all doses combined), which was significantly lower than the 12.3% annual rate of increase observed in six placebo-treated patients.

The reduction in brain atrophy was significantly correlated with improvement in clinical outcomes at 18 months on the Clinical Global Impression of Change and the cognitive subscale of the Alzheimer's Disease Assessment Scale. Baseline characteristics of the patients were not correlated with volumetric MRI outcomes.

“We are not encouraging people to use [IVIG] off-label for Alzheimer's disease, even though it has been safe and well tolerated in these small studies,” Dr. Relkin said in an interview. “It has never been studied in the Alzheimer's population before.”

“This is a 'kitchen sink' approach, so the next step is to find what is in [IVIG] that is causing the therapeutic effect.…We know that it has a fairly good complement of antiamyloid antibodies. Those are prime candidates, but we don't know for sure yet that those are the ones responsible for a therapeutic effect,” he said.

The ventricular enlargement rate was greater with placebo (left) than with IVIG (right).

Source Courtesy Dr. Dana Moore and Dr. Norman Relkin

Major Finding: Treatment with a range of doses of IVIG for 18 months resulted in a mean increase of 6.7% in lateral ventricular volume, which was significantly lower than the 12.3% increase observed with placebo.

Data Source: A double-blind, placebo-controlled, randomized phase II trial of 24 patients with mild-to-moderate Alzheimer's disease.

Disclosures: Baxter Healthcare, which produces Gammagard, the IVIG product used by the investigators, sponsored the study, with additional support from the Citigroup Foundation and the National Institutes of Health. Dr. Relkin reported receiving a research grant from Baxter Healthcare.

TORONTO — Intravenous immunoglobulin therapy reduced brain atrophy in patients with mild to moderate Alzheimer's disease in a small phase II trial. The finding suggests that specific IgG antibody components found in the blood product might be treatment candidates for the disease.

“Relative to what we have available right now [to treat Alzheimer's], this is a very promising outcome, and it's associated with a reduction in the rate of brain atrophy comparable to age-matched normals,” Dr. Norman Relkin said during a poster presentation at the annual meeting of the American Academy of Neurology. Enlargement of the cerebral lateral ventricles is known to occur as a consequence of brain atrophy in AD. This increase in ventricular volume is correlated with cognitive decline and increases in Alzheimer's disease neuropathology.

Dr. Relkin, who is the director of the Memory Disorders Program at New York-Presbyterian Hospital/Weill Cornell Medical Center, and his colleagues compared intravenous immunoglobulin (IVIG) therapy against placebo in a 6-month, double-blind, randomized study of 24 patients with mild to moderate AD.

In a 12-month extension phase of the study, 16 patients who originally were randomized to IVIG continued to receive the same doses of IVIG, whereas 8 placebo-treated patients were re-randomized to one of four doses of IVIG.

IVIG exhibited a dose-dependent effect on brain atrophy in which higher doses resulted in less atrophy. Among 14 IVIG-treated patients who underwent volumetric MRI at baseline and after 18 months, the yearly increase in lateral ventricle volume measured with volumetric MRI was lowest in patients treated with 0.4 mg/kg every 2 weeks (2.4%) and highest in those treated with 0.2 mg/kg every 2 weeks (11.2%).

The doses of IVIG that were given to patients ranged from 0.2 mg/kg every 2 weeks to 0.8 mg/kg every 4 weeks.

The volume of the lateral ventricles increased by a mean of 6.7% per year during treatment with IVIG (all doses combined), which was significantly lower than the 12.3% annual rate of increase observed in six placebo-treated patients.

The reduction in brain atrophy was significantly correlated with improvement in clinical outcomes at 18 months on the Clinical Global Impression of Change and the cognitive subscale of the Alzheimer's Disease Assessment Scale. Baseline characteristics of the patients were not correlated with volumetric MRI outcomes.

“We are not encouraging people to use [IVIG] off-label for Alzheimer's disease, even though it has been safe and well tolerated in these small studies,” Dr. Relkin said in an interview. “It has never been studied in the Alzheimer's population before.”

“This is a 'kitchen sink' approach, so the next step is to find what is in [IVIG] that is causing the therapeutic effect.…We know that it has a fairly good complement of antiamyloid antibodies. Those are prime candidates, but we don't know for sure yet that those are the ones responsible for a therapeutic effect,” he said.

The ventricular enlargement rate was greater with placebo (left) than with IVIG (right).

Source Courtesy Dr. Dana Moore and Dr. Norman Relkin

Major Finding: Treatment with a range of doses of IVIG for 18 months resulted in a mean increase of 6.7% in lateral ventricular volume, which was significantly lower than the 12.3% increase observed with placebo.

Data Source: A double-blind, randomized, placebo-controlled phase II trial of 24 patients with mild to moderate Alzheimer's disease.

Disclosures: Baxter Healthcare sponsored the study of IVIG, with additional support from the Citigroup Foundation and the National Institutes of Health. Dr. Relkin reporting no relevant disclosures besides receiving a research grant from Baxter Healthcare to study IVIG.

TORONTO — Intravenous immunoglobulin therapy reduced brain atrophy in patients with mild to moderate Alzheimer's disease in a small phase II trial. The finding suggests that specific IgG antibody components found in the blood product might be treatment candidates for the disease.

“Relative to what we have available right now [to treat Alzheimer's disease], this is a very promising outcome, and it's associated with a reduction in the rate of brain atrophy comparable to age-matched normals,” Dr. Norman Relkin said during a poster presentation at the annual meeting of the American Academy of Neurology.

Enlargement of the cerebral lateral ventricles is known to occur as a consequence of brain atrophy in Alzheimer's disease (AD). This increase in ventricular volume is correlated with cognitive decline and increases in Alzheimer's disease neuropathology.

Dr. Relkin and his colleagues compared intravenous immunoglobulin (IVIG) therapy against placebo in a 6-month, double-blind, randomized study of 24 patients with mild to moderate AD. In a 12-month extension phase of the study, 16 patients who originally were randomized to IVIG continued to receive the same doses of IVIG, whereas 8 placebo-treated patients were re-randomized to one of four doses of IVIG. The investigators used an IVIG product produced by Baxter Healthcare called Gammagard.

IVIG exhibited a dose-dependent effect on brain atrophy in which higher doses resulted in less atrophy. Among 14 IVIG-treated patients who underwent volumetric MRI at baseline and after 18 months, the yearly increase in lateral ventricle volume measured with volumetric MRI was lowest in patients treated with 0.4 mg/kg every 2 weeks (2.4%) and highest in those treated with 0.2 mg/kg every 2 weeks (11.2%). The doses of IVIG given to patients ranged from 0.2 mg/kg every 2 weeks to 0.8 mg/kg every 4 weeks.

The volume of the lateral ventricles increased by a mean of 6.7% per year during treatment with IVIG (all doses combined), which was significantly lower than the 12.3% annual rate of increase observed in six placebo-treated patients.

Only the 0.4-mg/kg dose of IVIG given every 2 weeks resulted in significantly less change in total brain volume than did treatment with placebo (−0.62% vs. −2.24%, respectively).

“In addition to the brain imaging, we have previously shown changes in cerebrospinal fluid and plasma amyloid levels …and levels of cerebral metabolism changing in response to treatment,” said Dr. Relkin, director of the Memory Disorders Program at New York–Presbyterian Hospital/Weill Cornell Medical Center.

The reduction in brain atrophy was significantly correlated with improvement in clinical outcomes at 18 months on the Clinical Global Impression of Change and the cognitive subscale of the Alzheimer's Disease Assessment Scale Baseline characteristics of the patients were not correlated with volumetric MRI outcomes.

Major Finding: Treatment with a range of doses of IVIG for 18 months resulted in a mean increase of 6.7% in lateral ventricular volume, which was significantly lower than the 12.3% increase observed with placebo.

Data Source: A double-blind, randomized, placebo-controlled phase II trial of 24 patients with mild to moderate Alzheimer's disease.

Disclosures: Baxter Healthcare sponsored the study of IVIG, with additional support from the Citigroup Foundation and the National Institutes of Health. Dr. Relkin reporting no relevant disclosures besides receiving a research grant from Baxter Healthcare to study IVIG.

TORONTO — Intravenous immunoglobulin therapy reduced brain atrophy in patients with mild to moderate Alzheimer's disease in a small phase II trial. The finding suggests that specific IgG antibody components found in the blood product might be treatment candidates for the disease.

“Relative to what we have available right now [to treat Alzheimer's disease], this is a very promising outcome, and it's associated with a reduction in the rate of brain atrophy comparable to age-matched normals,” Dr. Norman Relkin said during a poster presentation at the annual meeting of the American Academy of Neurology.

Enlargement of the cerebral lateral ventricles is known to occur as a consequence of brain atrophy in Alzheimer's disease (AD). This increase in ventricular volume is correlated with cognitive decline and increases in Alzheimer's disease neuropathology.

Dr. Relkin and his colleagues compared intravenous immunoglobulin (IVIG) therapy against placebo in a 6-month, double-blind, randomized study of 24 patients with mild to moderate AD. In a 12-month extension phase of the study, 16 patients who originally were randomized to IVIG continued to receive the same doses of IVIG, whereas 8 placebo-treated patients were re-randomized to one of four doses of IVIG. The investigators used an IVIG product produced by Baxter Healthcare called Gammagard.

IVIG exhibited a dose-dependent effect on brain atrophy in which higher doses resulted in less atrophy. Among 14 IVIG-treated patients who underwent volumetric MRI at baseline and after 18 months, the yearly increase in lateral ventricle volume measured with volumetric MRI was lowest in patients treated with 0.4 mg/kg every 2 weeks (2.4%) and highest in those treated with 0.2 mg/kg every 2 weeks (11.2%). The doses of IVIG given to patients ranged from 0.2 mg/kg every 2 weeks to 0.8 mg/kg every 4 weeks.

The volume of the lateral ventricles increased by a mean of 6.7% per year during treatment with IVIG (all doses combined), which was significantly lower than the 12.3% annual rate of increase observed in six placebo-treated patients.

Only the 0.4-mg/kg dose of IVIG given every 2 weeks resulted in significantly less change in total brain volume than did treatment with placebo (−0.62% vs. −2.24%, respectively).

“In addition to the brain imaging, we have previously shown changes in cerebrospinal fluid and plasma amyloid levels …and levels of cerebral metabolism changing in response to treatment,” said Dr. Relkin, director of the Memory Disorders Program at New York–Presbyterian Hospital/Weill Cornell Medical Center.

The reduction in brain atrophy was significantly correlated with improvement in clinical outcomes at 18 months on the Clinical Global Impression of Change and the cognitive subscale of the Alzheimer's Disease Assessment Scale Baseline characteristics of the patients were not correlated with volumetric MRI outcomes.

Major Finding: Treatment with a range of doses of IVIG for 18 months resulted in a mean increase of 6.7% in lateral ventricular volume, which was significantly lower than the 12.3% increase observed with placebo.

Data Source: A double-blind, randomized, placebo-controlled phase II trial of 24 patients with mild to moderate Alzheimer's disease.

Disclosures: Baxter Healthcare sponsored the study of IVIG, with additional support from the Citigroup Foundation and the National Institutes of Health. Dr. Relkin reporting no relevant disclosures besides receiving a research grant from Baxter Healthcare to study IVIG.

TORONTO — Intravenous immunoglobulin therapy reduced brain atrophy in patients with mild to moderate Alzheimer's disease in a small phase II trial. The finding suggests that specific IgG antibody components found in the blood product might be treatment candidates for the disease.

“Relative to what we have available right now [to treat Alzheimer's disease], this is a very promising outcome, and it's associated with a reduction in the rate of brain atrophy comparable to age-matched normals,” Dr. Norman Relkin said during a poster presentation at the annual meeting of the American Academy of Neurology.

Enlargement of the cerebral lateral ventricles is known to occur as a consequence of brain atrophy in Alzheimer's disease (AD). This increase in ventricular volume is correlated with cognitive decline and increases in Alzheimer's disease neuropathology.

Dr. Relkin and his colleagues compared intravenous immunoglobulin (IVIG) therapy against placebo in a 6-month, double-blind, randomized study of 24 patients with mild to moderate AD. In a 12-month extension phase of the study, 16 patients who originally were randomized to IVIG continued to receive the same doses of IVIG, whereas 8 placebo-treated patients were re-randomized to one of four doses of IVIG. The investigators used an IVIG product produced by Baxter Healthcare called Gammagard.

IVIG exhibited a dose-dependent effect on brain atrophy in which higher doses resulted in less atrophy. Among 14 IVIG-treated patients who underwent volumetric MRI at baseline and after 18 months, the yearly increase in lateral ventricle volume measured with volumetric MRI was lowest in patients treated with 0.4 mg/kg every 2 weeks (2.4%) and highest in those treated with 0.2 mg/kg every 2 weeks (11.2%). The doses of IVIG given to patients ranged from 0.2 mg/kg every 2 weeks to 0.8 mg/kg every 4 weeks.

The volume of the lateral ventricles increased by a mean of 6.7% per year during treatment with IVIG (all doses combined), which was significantly lower than the 12.3% annual rate of increase observed in six placebo-treated patients.

Only the 0.4-mg/kg dose of IVIG given every 2 weeks resulted in significantly less change in total brain volume than did treatment with placebo (−0.62% vs. −2.24%, respectively).

“In addition to the brain imaging, we have previously shown changes in cerebrospinal fluid and plasma amyloid levels …and levels of cerebral metabolism changing in response to treatment,” said Dr. Relkin, director of the Memory Disorders Program at New York–Presbyterian Hospital/Weill Cornell Medical Center.

The reduction in brain atrophy was significantly correlated with improvement in clinical outcomes at 18 months on the Clinical Global Impression of Change and the cognitive subscale of the Alzheimer's Disease Assessment Scale Baseline characteristics of the patients were not correlated with volumetric MRI outcomes.

WASHINGTON — More often than not, elderly patients who fall in long-term care facilities do not trip or stumble while walking, but rather are transitioning from standing still or initiating a new activity at the time of their fall, according to an analysis of video-recorded falls.

“These results challenge traditional assumptions regarding the cause and circumstance of falls in older adults living in long-term care,” Stephen N. Robinovitch, Ph.D., said at the meeting.

About half of older adults living in long-term care facilities fall each year, whereas the annual incidence is about 30% among older adults living in the community, said Dr. Robinovitch of the department of biomedical physiology and kinesiology at Simon Fraser University, Burnaby, B.C.

Studies of self-reported falls have suggested that about half of all falls result from slips and trips, while the rest are ascribed to losing balance, changing posture, or a leg giving way. In these studies, the most common activities at the time of a fall were walking, turning, transferring, and reaching.

As part of the ongoing Vancouver Fall Mechanisms Study, Dr. Robinovitch and his colleagues are working with two long-term care facilities in British Columbia to develop “real-life laboratories” where they can witness activity before and during falls instead of relying on self-reports.

In common areas throughout the two facilities (each with about 230 beds), the investigators used 270 digital video cameras to record 184 falls by 124 residents during a 2-year period. Three expert reviewers classified the key characteristics of each fall. “A lot of what our data are suggesting is that falls among this population are highly variable,” Dr. Robinovitch said in an interview.

Unlike previous studies of falls, the videos indicated that an incorrect transfer of weight caused most falls (51%). Trips were estimated to account for 22% of falls, and slips for only 4%. Hitting or bumping something caused 21% of falls, collapsing was to blame in 10% of falls, and losing support from an external object was the cause in 13%. Each fall could have multiple causes. At the time of a fall, four activities were significantly more common than others: walking forward (26%), standing quietly (22%), sitting down or lowering (16%), and initiating walking (16%).

Initial fall direction was equally divided among forward, backward, and sideways, but many fallers turned during descent, causing backward landings to be more common than forward or sideways impacts. The video analysis revealed that a fall starting forward is just as likely as a sideways fall to result in an impact to the hip.

Dr. Robinovitch noted that many older adults, especially older women, are unable to react quickly enough to take a corrective step or can't break a fall with their hands. In the video study, residents hit their head in 30% of falls, their hip in 46%, and their hands in 54%.

Impact to the hands did not affect the probability of impact to the head, suggesting that although older adults do use their hands to arrest a fall, strengthening exercises are warranted to improve the effect of this response, he said.

At youtube.com/ElsGlobalMedicalNews

WASHINGTON — More often than not, elderly patients who fall in long-term care facilities do not trip or stumble while walking, but rather are transitioning from standing still or initiating a new activity at the time of their fall, according to an analysis of video-recorded falls.

“These results challenge traditional assumptions regarding the cause and circumstance of falls in older adults living in long-term care,” Stephen N. Robinovitch, Ph.D., said at the meeting.

About half of older adults living in long-term care facilities fall each year, whereas the annual incidence is about 30% among older adults living in the community, said Dr. Robinovitch of the department of biomedical physiology and kinesiology at Simon Fraser University, Burnaby, B.C.

Studies of self-reported falls have suggested that about half of all falls result from slips and trips, while the rest are ascribed to losing balance, changing posture, or a leg giving way. In these studies, the most common activities at the time of a fall were walking, turning, transferring, and reaching.

As part of the ongoing Vancouver Fall Mechanisms Study, Dr. Robinovitch and his colleagues are working with two long-term care facilities in British Columbia to develop “real-life laboratories” where they can witness activity before and during falls instead of relying on self-reports.

In common areas throughout the two facilities (each with about 230 beds), the investigators used 270 digital video cameras to record 184 falls by 124 residents during a 2-year period. Three expert reviewers classified the key characteristics of each fall. “A lot of what our data are suggesting is that falls among this population are highly variable,” Dr. Robinovitch said in an interview.

Unlike previous studies of falls, the videos indicated that an incorrect transfer of weight caused most falls (51%). Trips were estimated to account for 22% of falls, and slips for only 4%. Hitting or bumping something caused 21% of falls, collapsing was to blame in 10% of falls, and losing support from an external object was the cause in 13%. Each fall could have multiple causes. At the time of a fall, four activities were significantly more common than others: walking forward (26%), standing quietly (22%), sitting down or lowering (16%), and initiating walking (16%).

Initial fall direction was equally divided among forward, backward, and sideways, but many fallers turned during descent, causing backward landings to be more common than forward or sideways impacts. The video analysis revealed that a fall starting forward is just as likely as a sideways fall to result in an impact to the hip.

Dr. Robinovitch noted that many older adults, especially older women, are unable to react quickly enough to take a corrective step or can't break a fall with their hands. In the video study, residents hit their head in 30% of falls, their hip in 46%, and their hands in 54%.

Impact to the hands did not affect the probability of impact to the head, suggesting that although older adults do use their hands to arrest a fall, strengthening exercises are warranted to improve the effect of this response, he said.

At youtube.com/ElsGlobalMedicalNews

WASHINGTON — More often than not, elderly patients who fall in long-term care facilities do not trip or stumble while walking, but rather are transitioning from standing still or initiating a new activity at the time of their fall, according to an analysis of video-recorded falls.

“These results challenge traditional assumptions regarding the cause and circumstance of falls in older adults living in long-term care,” Stephen N. Robinovitch, Ph.D., said at the meeting.

About half of older adults living in long-term care facilities fall each year, whereas the annual incidence is about 30% among older adults living in the community, said Dr. Robinovitch of the department of biomedical physiology and kinesiology at Simon Fraser University, Burnaby, B.C.

Studies of self-reported falls have suggested that about half of all falls result from slips and trips, while the rest are ascribed to losing balance, changing posture, or a leg giving way. In these studies, the most common activities at the time of a fall were walking, turning, transferring, and reaching.

As part of the ongoing Vancouver Fall Mechanisms Study, Dr. Robinovitch and his colleagues are working with two long-term care facilities in British Columbia to develop “real-life laboratories” where they can witness activity before and during falls instead of relying on self-reports.

In common areas throughout the two facilities (each with about 230 beds), the investigators used 270 digital video cameras to record 184 falls by 124 residents during a 2-year period. Three expert reviewers classified the key characteristics of each fall. “A lot of what our data are suggesting is that falls among this population are highly variable,” Dr. Robinovitch said in an interview.

Unlike previous studies of falls, the videos indicated that an incorrect transfer of weight caused most falls (51%). Trips were estimated to account for 22% of falls, and slips for only 4%. Hitting or bumping something caused 21% of falls, collapsing was to blame in 10% of falls, and losing support from an external object was the cause in 13%. Each fall could have multiple causes. At the time of a fall, four activities were significantly more common than others: walking forward (26%), standing quietly (22%), sitting down or lowering (16%), and initiating walking (16%).

Initial fall direction was equally divided among forward, backward, and sideways, but many fallers turned during descent, causing backward landings to be more common than forward or sideways impacts. The video analysis revealed that a fall starting forward is just as likely as a sideways fall to result in an impact to the hip.

Dr. Robinovitch noted that many older adults, especially older women, are unable to react quickly enough to take a corrective step or can't break a fall with their hands. In the video study, residents hit their head in 30% of falls, their hip in 46%, and their hands in 54%.

Impact to the hands did not affect the probability of impact to the head, suggesting that although older adults do use their hands to arrest a fall, strengthening exercises are warranted to improve the effect of this response, he said.

At youtube.com/ElsGlobalMedicalNews

Healthy term infants and their mothers should receive individualized care during their hospital stay, but pediatricians, obstetricians, nurses, and other health care providers should work together to determine the optimal time for hospital discharge for each mother-infant dyad, according to a policy statement issued by the American Academy of Pediatrics.

“There have been new studies since [the previous policy statement was published in 2004] to find out if there are better ways to assess the readiness for discharge of a healthy term infant, and these studies have shown that perceptions of readiness or unreadiness at the time of discharge often differ among pediatricians, obstetricians, and mothers,” said lead author and neonatologist Praveen Kumar of Northwestern University, Chicago.

The new statement recommends that “the hospital stay of the mother and her healthy term newborn infant should be long enough to allow identification of early problems and to ensure that the family is able and prepared to care for the infant at home.”

Dr. Kumar and eight other members of the AAP's Committee on Fetus and Newborn wrote the statement, which recommends following a set of 16 minimum criteria before discharging a term newborn (Pediatrics 2010;125:405-9).

“It is our recommendation that all hospitals should develop guidelines in collaboration with appropriate community agencies and third-party payers, to establish hospital-stay and follow-up programs for healthy term infants that implement these recommendations,” Dr. Kumar said in an interview.

The statement also recommends that physicians use the AAP's Safe and Healthy Beginnings toolkit, which contains a discharge readiness checklist that can aid clinicians with the preparation of a newborn for discharge (http://practice.aap.org/public/Newborn_Discharge_SAMPLE.pdf

In making discharge assessments, the committee advises determining that the clinical course and physical examination of the newborn reveal no abnormalities that require additional hospitalization; vital signs are within normal ranges; and there is a history of successful feedings, urinations, and bowel movements and a lack of significant circumcisional bleeding. Other examinations should assess for the clinical risk of hyperbilirubinemia, and for sepsis based on maternal risk factors and in accord with guidelines for preventing perinatal group B streptococcal disease.

Testing of newborns' blood type as well as their cord blood should be performed as clinically indicated. Hospital protocols and state regulations may call for other metabolic and hearing screenings. The initial hepatitis B vaccine also should be administered to the newborn according to the current immunization schedule.

Mothers should have certain blood tests performed, including screening tests for syphilis and hepatitis B surface antigen and other tests required by state regulations, such as HIV testing. Other assessments need to be made of the mother's knowledge, ability, and confidence to provide adequate care for her infant—including barriers to adequate follow-up care for the newborn—as well as any family, environmental, and social risk factors.

“One of the take-home messages is that the length of stay should accommodate the unique characteristics of each mother-infant dyad, including the health of the mother, the health and stability of the infant, the ability and confidence of the mother to care for her infant, the adequacy of support systems at home, and access to appropriate follow-up care.

To accomplish this, a pediatrician's decision to discharge a newborn should be made jointly with input from the mother, her obstetrician, and other health care providers who are involved in the care of the mother and her infant, such as nursing staff and social workers,” Dr. Kumar said.

“Everything should be considered as a mother-infant dyad rather than independently for the mother and infant. Just looking at the baby and making a decision that the baby can go home” is not adequate, he added.

Once a medical home for the newborn has been identified and a plan for timely communication of pertinent clinical information to the medical home is in place, the committee recommends making a follow-up appointment for the infant within 48 hours of discharge, but no later than 72 hours, if the infant was discharged less than 48 hours after delivery.

“It is very important for all babies to have a medical home, and it should be in place before a baby goes home,” Dr. Kumar said.

Disclosures: None was reported.

The new policy recommends following 16 minimum criteria before discharge.

Source ©Gary Martin/istockphoto.com

Healthy term infants and their mothers should receive individualized care during their hospital stay, but pediatricians, obstetricians, nurses, and other health care providers should work together to determine the optimal time for hospital discharge for each mother-infant dyad, according to a policy statement issued by the American Academy of Pediatrics.

“There have been new studies since [the previous policy statement was published in 2004] to find out if there are better ways to assess the readiness for discharge of a healthy term infant, and these studies have shown that perceptions of readiness or unreadiness at the time of discharge often differ among pediatricians, obstetricians, and mothers,” said lead author and neonatologist Praveen Kumar of Northwestern University, Chicago.

The new statement recommends that “the hospital stay of the mother and her healthy term newborn infant should be long enough to allow identification of early problems and to ensure that the family is able and prepared to care for the infant at home.”

Dr. Kumar and eight other members of the AAP's Committee on Fetus and Newborn wrote the statement, which recommends following a set of 16 minimum criteria before discharging a term newborn (Pediatrics 2010;125:405-9).

“It is our recommendation that all hospitals should develop guidelines in collaboration with appropriate community agencies and third-party payers, to establish hospital-stay and follow-up programs for healthy term infants that implement these recommendations,” Dr. Kumar said in an interview.

The statement also recommends that physicians use the AAP's Safe and Healthy Beginnings toolkit, which contains a discharge readiness checklist that can aid clinicians with the preparation of a newborn for discharge (http://practice.aap.org/public/Newborn_Discharge_SAMPLE.pdf

In making discharge assessments, the committee advises determining that the clinical course and physical examination of the newborn reveal no abnormalities that require additional hospitalization; vital signs are within normal ranges; and there is a history of successful feedings, urinations, and bowel movements and a lack of significant circumcisional bleeding. Other examinations should assess for the clinical risk of hyperbilirubinemia, and for sepsis based on maternal risk factors and in accord with guidelines for preventing perinatal group B streptococcal disease.

Testing of newborns' blood type as well as their cord blood should be performed as clinically indicated. Hospital protocols and state regulations may call for other metabolic and hearing screenings. The initial hepatitis B vaccine also should be administered to the newborn according to the current immunization schedule.

Mothers should have certain blood tests performed, including screening tests for syphilis and hepatitis B surface antigen and other tests required by state regulations, such as HIV testing. Other assessments need to be made of the mother's knowledge, ability, and confidence to provide adequate care for her infant—including barriers to adequate follow-up care for the newborn—as well as any family, environmental, and social risk factors.

“One of the take-home messages is that the length of stay should accommodate the unique characteristics of each mother-infant dyad, including the health of the mother, the health and stability of the infant, the ability and confidence of the mother to care for her infant, the adequacy of support systems at home, and access to appropriate follow-up care.

To accomplish this, a pediatrician's decision to discharge a newborn should be made jointly with input from the mother, her obstetrician, and other health care providers who are involved in the care of the mother and her infant, such as nursing staff and social workers,” Dr. Kumar said.

“Everything should be considered as a mother-infant dyad rather than independently for the mother and infant. Just looking at the baby and making a decision that the baby can go home” is not adequate, he added.

Once a medical home for the newborn has been identified and a plan for timely communication of pertinent clinical information to the medical home is in place, the committee recommends making a follow-up appointment for the infant within 48 hours of discharge, but no later than 72 hours, if the infant was discharged less than 48 hours after delivery.

“It is very important for all babies to have a medical home, and it should be in place before a baby goes home,” Dr. Kumar said.

Disclosures: None was reported.

The new policy recommends following 16 minimum criteria before discharge.

Source ©Gary Martin/istockphoto.com

Healthy term infants and their mothers should receive individualized care during their hospital stay, but pediatricians, obstetricians, nurses, and other health care providers should work together to determine the optimal time for hospital discharge for each mother-infant dyad, according to a policy statement issued by the American Academy of Pediatrics.

“There have been new studies since [the previous policy statement was published in 2004] to find out if there are better ways to assess the readiness for discharge of a healthy term infant, and these studies have shown that perceptions of readiness or unreadiness at the time of discharge often differ among pediatricians, obstetricians, and mothers,” said lead author and neonatologist Praveen Kumar of Northwestern University, Chicago.

The new statement recommends that “the hospital stay of the mother and her healthy term newborn infant should be long enough to allow identification of early problems and to ensure that the family is able and prepared to care for the infant at home.”

Dr. Kumar and eight other members of the AAP's Committee on Fetus and Newborn wrote the statement, which recommends following a set of 16 minimum criteria before discharging a term newborn (Pediatrics 2010;125:405-9).

“It is our recommendation that all hospitals should develop guidelines in collaboration with appropriate community agencies and third-party payers, to establish hospital-stay and follow-up programs for healthy term infants that implement these recommendations,” Dr. Kumar said in an interview.

The statement also recommends that physicians use the AAP's Safe and Healthy Beginnings toolkit, which contains a discharge readiness checklist that can aid clinicians with the preparation of a newborn for discharge (http://practice.aap.org/public/Newborn_Discharge_SAMPLE.pdf

In making discharge assessments, the committee advises determining that the clinical course and physical examination of the newborn reveal no abnormalities that require additional hospitalization; vital signs are within normal ranges; and there is a history of successful feedings, urinations, and bowel movements and a lack of significant circumcisional bleeding. Other examinations should assess for the clinical risk of hyperbilirubinemia, and for sepsis based on maternal risk factors and in accord with guidelines for preventing perinatal group B streptococcal disease.

Testing of newborns' blood type as well as their cord blood should be performed as clinically indicated. Hospital protocols and state regulations may call for other metabolic and hearing screenings. The initial hepatitis B vaccine also should be administered to the newborn according to the current immunization schedule.

Mothers should have certain blood tests performed, including screening tests for syphilis and hepatitis B surface antigen and other tests required by state regulations, such as HIV testing. Other assessments need to be made of the mother's knowledge, ability, and confidence to provide adequate care for her infant—including barriers to adequate follow-up care for the newborn—as well as any family, environmental, and social risk factors.

“One of the take-home messages is that the length of stay should accommodate the unique characteristics of each mother-infant dyad, including the health of the mother, the health and stability of the infant, the ability and confidence of the mother to care for her infant, the adequacy of support systems at home, and access to appropriate follow-up care.

To accomplish this, a pediatrician's decision to discharge a newborn should be made jointly with input from the mother, her obstetrician, and other health care providers who are involved in the care of the mother and her infant, such as nursing staff and social workers,” Dr. Kumar said.

“Everything should be considered as a mother-infant dyad rather than independently for the mother and infant. Just looking at the baby and making a decision that the baby can go home” is not adequate, he added.

Once a medical home for the newborn has been identified and a plan for timely communication of pertinent clinical information to the medical home is in place, the committee recommends making a follow-up appointment for the infant within 48 hours of discharge, but no later than 72 hours, if the infant was discharged less than 48 hours after delivery.

“It is very important for all babies to have a medical home, and it should be in place before a baby goes home,” Dr. Kumar said.

Disclosures: None was reported.

The new policy recommends following 16 minimum criteria before discharge.

Source ©Gary Martin/istockphoto.com

Major Finding: A nasal wash lactate dehydrogenase level reaching 365 U/mL or higher in children with bronchiolitis was associated with a significant 81% reduction in the need for hospital admission.

Data Source: A retrospective analysis of prospectively collected nasal wash samples from 98 children with bronchiolitis.

Disclosures: The study was funded by a grant from the National Institutes of Health Baylor Research Training Program for Pediatricians and a Viral Respiratory Pathogen Research Unit Contract. Dr. Laham and his associates said they had no relevant financial conflicts to disclose.

The concentration of lactate dehydrogenase in nasal wash may be a useful clinical biochemical marker of the severity of bronchiolitis in children and help to determine their need for hospitalization, the results of a retrospective analysis suggest.

Dr. Federico R. Laham and his colleagues at Baylor College of Medicine, Houston, found that bronchiolitic children with lower lactate dehydrogenase (LDH) levels in their nasal wash were significantly more likely to leave the emergency department without being hospitalized and to have a shorter duration of oxygen supplementation or no need for it than were children who had higher LDH levels.

“Currently the presence of hypoxia, significant respiratory distress, and clinical judgment are the main consideration[s] for determining the need to hospitalize a child with bronchiolitis. Having a validated biochemical marker predictive for hospitalization can provide another objective parameter to the physician, and would be valuable in difficult-to-assess cases,” Dr. Laham and his associates wrote (Pediatrics 2010;125:e225–33).

The study represents the first known analysis of lactate dehydrogenase levels in nasal wash, according to the investigators. They identified viruses, tested for cytokines and chemokines, and measured levels of apoptosis and LDH in nasal wash specimens from 98 children who had participated in an earlier study of bronchiolitis. They also measured serum LDH levels. These 98 patients had a median age of 5.6 months and a median duration of illness of 4 days at the time of their presentation to the ED.

Respiratory syncytial virus (RSV) was identified in 65 (66%) patients, including 15 coinfected with RSV and another virus. Although detection of a virus alone was associated with a higher concentration of LDH in nasal wash, children with RSV infection in particular had a significantly greater LDH level in nasal wash than did children not infected with RSV.

A higher nasal wash to serum LDH ratio in children sent home from the ED, compared with those admitted to the hospital, supports the hypothesis that “LDH originates from widespread airway epithelial cell injury and apoptosis or from leukocytes (largely polymorphonuclear cells) present in the [nasal wash] fluid.”

Dr. Laham and his colleagues noted that previous studies investigating the risk of hospitalization and the severity of disease in children with RSV infection largely corroborate these results and “support the concept of a protective effect derived from a robust innate immune response during an episode of RSV bronchiolitis, where inflammatory markers inversely correlated with disease severity.”

In a multivariate analysis, an age of 3 months or younger, the need for intravenous fluids, and the presence of hypoxia were significant predictors of hospitalization among children with bronchiolitis who presented to the ED.

However, a nasal wash LDH level reaching 365 U/mL or higher was associated with a significant 81% reduction in the need for admission.

In the same prediction model, the investigators calculated an area under the receiver operating characteristic curve of 0.87. Based on that area and a cutoff value of 0.5 for the predicted probability of hospitalization, the model predicted hospitalization with 81% sensitivity and 77% specificity.

“These values are comparable to many of the point-of-care tests used in diagnosing a viral infection. The LDH assay is easy to perform, inexpensive, and available in most clinical laboratories. At our institution, the expected turnaround time for serum LDH is 1 hour, and [nasal wash] samples should not be treated differently,” Dr. Laham and his associates wrote.

Major Finding: A nasal wash lactate dehydrogenase level reaching 365 U/mL or higher in children with bronchiolitis was associated with a significant 81% reduction in the need for hospital admission.

Data Source: A retrospective analysis of prospectively collected nasal wash samples from 98 children with bronchiolitis.

Disclosures: The study was funded by a grant from the National Institutes of Health Baylor Research Training Program for Pediatricians and a Viral Respiratory Pathogen Research Unit Contract. Dr. Laham and his associates said they had no relevant financial conflicts to disclose.

The concentration of lactate dehydrogenase in nasal wash may be a useful clinical biochemical marker of the severity of bronchiolitis in children and help to determine their need for hospitalization, the results of a retrospective analysis suggest.

Dr. Federico R. Laham and his colleagues at Baylor College of Medicine, Houston, found that bronchiolitic children with lower lactate dehydrogenase (LDH) levels in their nasal wash were significantly more likely to leave the emergency department without being hospitalized and to have a shorter duration of oxygen supplementation or no need for it than were children who had higher LDH levels.

“Currently the presence of hypoxia, significant respiratory distress, and clinical judgment are the main consideration[s] for determining the need to hospitalize a child with bronchiolitis. Having a validated biochemical marker predictive for hospitalization can provide another objective parameter to the physician, and would be valuable in difficult-to-assess cases,” Dr. Laham and his associates wrote (Pediatrics 2010;125:e225–33).

The study represents the first known analysis of lactate dehydrogenase levels in nasal wash, according to the investigators. They identified viruses, tested for cytokines and chemokines, and measured levels of apoptosis and LDH in nasal wash specimens from 98 children who had participated in an earlier study of bronchiolitis. They also measured serum LDH levels. These 98 patients had a median age of 5.6 months and a median duration of illness of 4 days at the time of their presentation to the ED.

Respiratory syncytial virus (RSV) was identified in 65 (66%) patients, including 15 coinfected with RSV and another virus. Although detection of a virus alone was associated with a higher concentration of LDH in nasal wash, children with RSV infection in particular had a significantly greater LDH level in nasal wash than did children not infected with RSV.

A higher nasal wash to serum LDH ratio in children sent home from the ED, compared with those admitted to the hospital, supports the hypothesis that “LDH originates from widespread airway epithelial cell injury and apoptosis or from leukocytes (largely polymorphonuclear cells) present in the [nasal wash] fluid.”

Dr. Laham and his colleagues noted that previous studies investigating the risk of hospitalization and the severity of disease in children with RSV infection largely corroborate these results and “support the concept of a protective effect derived from a robust innate immune response during an episode of RSV bronchiolitis, where inflammatory markers inversely correlated with disease severity.”

In a multivariate analysis, an age of 3 months or younger, the need for intravenous fluids, and the presence of hypoxia were significant predictors of hospitalization among children with bronchiolitis who presented to the ED.

However, a nasal wash LDH level reaching 365 U/mL or higher was associated with a significant 81% reduction in the need for admission.

In the same prediction model, the investigators calculated an area under the receiver operating characteristic curve of 0.87. Based on that area and a cutoff value of 0.5 for the predicted probability of hospitalization, the model predicted hospitalization with 81% sensitivity and 77% specificity.

“These values are comparable to many of the point-of-care tests used in diagnosing a viral infection. The LDH assay is easy to perform, inexpensive, and available in most clinical laboratories. At our institution, the expected turnaround time for serum LDH is 1 hour, and [nasal wash] samples should not be treated differently,” Dr. Laham and his associates wrote.

Major Finding: A nasal wash lactate dehydrogenase level reaching 365 U/mL or higher in children with bronchiolitis was associated with a significant 81% reduction in the need for hospital admission.

Data Source: A retrospective analysis of prospectively collected nasal wash samples from 98 children with bronchiolitis.

Disclosures: The study was funded by a grant from the National Institutes of Health Baylor Research Training Program for Pediatricians and a Viral Respiratory Pathogen Research Unit Contract. Dr. Laham and his associates said they had no relevant financial conflicts to disclose.

The concentration of lactate dehydrogenase in nasal wash may be a useful clinical biochemical marker of the severity of bronchiolitis in children and help to determine their need for hospitalization, the results of a retrospective analysis suggest.

Dr. Federico R. Laham and his colleagues at Baylor College of Medicine, Houston, found that bronchiolitic children with lower lactate dehydrogenase (LDH) levels in their nasal wash were significantly more likely to leave the emergency department without being hospitalized and to have a shorter duration of oxygen supplementation or no need for it than were children who had higher LDH levels.

“Currently the presence of hypoxia, significant respiratory distress, and clinical judgment are the main consideration[s] for determining the need to hospitalize a child with bronchiolitis. Having a validated biochemical marker predictive for hospitalization can provide another objective parameter to the physician, and would be valuable in difficult-to-assess cases,” Dr. Laham and his associates wrote (Pediatrics 2010;125:e225–33).

The study represents the first known analysis of lactate dehydrogenase levels in nasal wash, according to the investigators. They identified viruses, tested for cytokines and chemokines, and measured levels of apoptosis and LDH in nasal wash specimens from 98 children who had participated in an earlier study of bronchiolitis. They also measured serum LDH levels. These 98 patients had a median age of 5.6 months and a median duration of illness of 4 days at the time of their presentation to the ED.

Respiratory syncytial virus (RSV) was identified in 65 (66%) patients, including 15 coinfected with RSV and another virus. Although detection of a virus alone was associated with a higher concentration of LDH in nasal wash, children with RSV infection in particular had a significantly greater LDH level in nasal wash than did children not infected with RSV.

A higher nasal wash to serum LDH ratio in children sent home from the ED, compared with those admitted to the hospital, supports the hypothesis that “LDH originates from widespread airway epithelial cell injury and apoptosis or from leukocytes (largely polymorphonuclear cells) present in the [nasal wash] fluid.”

Dr. Laham and his colleagues noted that previous studies investigating the risk of hospitalization and the severity of disease in children with RSV infection largely corroborate these results and “support the concept of a protective effect derived from a robust innate immune response during an episode of RSV bronchiolitis, where inflammatory markers inversely correlated with disease severity.”

In a multivariate analysis, an age of 3 months or younger, the need for intravenous fluids, and the presence of hypoxia were significant predictors of hospitalization among children with bronchiolitis who presented to the ED.

However, a nasal wash LDH level reaching 365 U/mL or higher was associated with a significant 81% reduction in the need for admission.

In the same prediction model, the investigators calculated an area under the receiver operating characteristic curve of 0.87. Based on that area and a cutoff value of 0.5 for the predicted probability of hospitalization, the model predicted hospitalization with 81% sensitivity and 77% specificity.

“These values are comparable to many of the point-of-care tests used in diagnosing a viral infection. The LDH assay is easy to perform, inexpensive, and available in most clinical laboratories. At our institution, the expected turnaround time for serum LDH is 1 hour, and [nasal wash] samples should not be treated differently,” Dr. Laham and his associates wrote.

Healthy term infants and their mothers should receive individualized care during their hospital stay, but pediatricians, obstetricians, nurses, and other health care providers should work together to determine the optimal time for hospital discharge for each mother-infant dyad, according to a policy statement issued by the American Academy of Pediatrics.

“There have been new studies since [the previous policy statement was published in 2004] to find out if there are better ways to assess the readiness for discharge of a healthy term infant, and these studies have shown that perceptions of readiness or unreadiness at the time of discharge often differ among pediatricians, obstetricians, and mothers,” said lead author Dr. Praveen Kumar, a neonatologist at Northwestern University, Chicago.

The new statement recommends that “the hospital stay of the mother and her healthy term newborn infant should be long enough to allow identification of early problems and to ensure that the family is able and prepared to care for the infant at home.”

Dr. Kumar and eight other members of the AAP's Committee on Fetus and Newborn wrote the statement, which recommends following a set of 16 minimum criteria before discharging a term newborn (Pediatrics 2010;125:405-9).

“It is our recommendation that all hospitals should develop guidelines in collaboration with appropriate community agencies and third-party payers, to establish hospital-stay and follow-up programs for healthy term infants that implement these recommendations,” Dr. Kumar said in an interview.

The statement also recommends that physicians use the AAP's Safe and Healthy Beginnings toolkit, which contains a discharge readiness checklist (http://practice.aap.org/public/Newborn_Discharge_SAMPLE.pdf

In making discharge assessments, the committee advises determining that the clinical course and physical examination of the newborn reveal no abnormalities that require additional hospitalization, vital signs are within normal ranges, and there is a history of successful feedings, urinations, and bowel movements and a lack of significant circumcisional bleeding. Other examinations should assess for the clinical risk of hyperbilirubinemia, and for sepsis based on maternal risk factors and in accord with guidelines for preventing perinatal group B streptococcal disease.

Testing of newborns' blood type as well as their cord blood should be performed as clinically indicated. Hospital protocols and state regulations may call for other metabolic and hearing screenings. The newborn should receive the initial hepatitis B vaccine according to the current immunization schedule.

Mothers should have certain blood tests performed, including screening tests for syphilis and hepatitis B surface antigen and other tests required by state regulations, such as HIV testing. Other assessments should consider the mother's knowledge, ability, and confidence to provide adequate care for her infant—including barriers to adequate follow-up care for the newborn—as well as family, environmental, and social risk factors.

“The length of stay should accommodate the unique characteristics of each mother-infant dyad, including the health of the mother, the health and stability of the infant, the ability and confidence of the mother to care for her infant, the adequacy of support systems at home, and access to appropriate follow-up care,” Dr. Kumar said. The decision to discharge a newborn should be made jointly with input from the mother, her obstetrician, and nursing staff, social workers, and other health care providers involved in the care of the mother and her infant.

Once a medical home for the newborn has been identified and a plan for timely communication of clinical information to the medical home is in place, the committee recommends making a follow-up appointment for the infant within 48 hours of discharge, but no later than 72 hours, if the infant was discharged less than 48 hours after delivery.

Disclosures: Dr. Kumar said he had no relevant disclosures to report.

My Take

Caring for the Mother-Infant Dyad

The recommendations in the American Academy of Pediatrics policy statement should be considered in the discharge management of any healthy term infant. Hopefully, many of the guidelines are being implemented already in most nurseries.

Pediatric hospitalists are in a unique position to be advocates in the care of the mother-infant dyad. Pediatric hospitalists can assess the medical needs of the infant and observe how the mother interacts with the infant. In their administrative role, pediatric hospitalists also can support quality improvement efforts related to the nursery and to the care of the mother-infant dyad.

We also need to recognize the importance of establishing the medical home for meeting the ongoing medical and social needs of the newborn and mother, and for eliminating potential barriers to adequate follow-up care.

Implementing these minimum requirements for quality care in the newborn nursery may appear challenging, but it's well worth the effort and not as arduous as it may appear. The AAP's Safe and Healthy Beginnings toolkit is a good place to start.

SCOTT BEICHNER, D.O., is a pediatric hospitalist at the Cleveland Clinic Children's Hospital. He has no conflicts of interest to report.

Healthy term infants and their mothers should receive individualized care during their hospital stay, but pediatricians, obstetricians, nurses, and other health care providers should work together to determine the optimal time for hospital discharge for each mother-infant dyad, according to a policy statement issued by the American Academy of Pediatrics.

“There have been new studies since [the previous policy statement was published in 2004] to find out if there are better ways to assess the readiness for discharge of a healthy term infant, and these studies have shown that perceptions of readiness or unreadiness at the time of discharge often differ among pediatricians, obstetricians, and mothers,” said lead author Dr. Praveen Kumar, a neonatologist at Northwestern University, Chicago.

The new statement recommends that “the hospital stay of the mother and her healthy term newborn infant should be long enough to allow identification of early problems and to ensure that the family is able and prepared to care for the infant at home.”

Dr. Kumar and eight other members of the AAP's Committee on Fetus and Newborn wrote the statement, which recommends following a set of 16 minimum criteria before discharging a term newborn (Pediatrics 2010;125:405-9).

“It is our recommendation that all hospitals should develop guidelines in collaboration with appropriate community agencies and third-party payers, to establish hospital-stay and follow-up programs for healthy term infants that implement these recommendations,” Dr. Kumar said in an interview.

The statement also recommends that physicians use the AAP's Safe and Healthy Beginnings toolkit, which contains a discharge readiness checklist (http://practice.aap.org/public/Newborn_Discharge_SAMPLE.pdf

In making discharge assessments, the committee advises determining that the clinical course and physical examination of the newborn reveal no abnormalities that require additional hospitalization, vital signs are within normal ranges, and there is a history of successful feedings, urinations, and bowel movements and a lack of significant circumcisional bleeding. Other examinations should assess for the clinical risk of hyperbilirubinemia, and for sepsis based on maternal risk factors and in accord with guidelines for preventing perinatal group B streptococcal disease.

Testing of newborns' blood type as well as their cord blood should be performed as clinically indicated. Hospital protocols and state regulations may call for other metabolic and hearing screenings. The newborn should receive the initial hepatitis B vaccine according to the current immunization schedule.

Mothers should have certain blood tests performed, including screening tests for syphilis and hepatitis B surface antigen and other tests required by state regulations, such as HIV testing. Other assessments should consider the mother's knowledge, ability, and confidence to provide adequate care for her infant—including barriers to adequate follow-up care for the newborn—as well as family, environmental, and social risk factors.

“The length of stay should accommodate the unique characteristics of each mother-infant dyad, including the health of the mother, the health and stability of the infant, the ability and confidence of the mother to care for her infant, the adequacy of support systems at home, and access to appropriate follow-up care,” Dr. Kumar said. The decision to discharge a newborn should be made jointly with input from the mother, her obstetrician, and nursing staff, social workers, and other health care providers involved in the care of the mother and her infant.

Once a medical home for the newborn has been identified and a plan for timely communication of clinical information to the medical home is in place, the committee recommends making a follow-up appointment for the infant within 48 hours of discharge, but no later than 72 hours, if the infant was discharged less than 48 hours after delivery.

Disclosures: Dr. Kumar said he had no relevant disclosures to report.

My Take

Caring for the Mother-Infant Dyad

The recommendations in the American Academy of Pediatrics policy statement should be considered in the discharge management of any healthy term infant. Hopefully, many of the guidelines are being implemented already in most nurseries.

Pediatric hospitalists are in a unique position to be advocates in the care of the mother-infant dyad. Pediatric hospitalists can assess the medical needs of the infant and observe how the mother interacts with the infant. In their administrative role, pediatric hospitalists also can support quality improvement efforts related to the nursery and to the care of the mother-infant dyad.

We also need to recognize the importance of establishing the medical home for meeting the ongoing medical and social needs of the newborn and mother, and for eliminating potential barriers to adequate follow-up care.

Implementing these minimum requirements for quality care in the newborn nursery may appear challenging, but it's well worth the effort and not as arduous as it may appear. The AAP's Safe and Healthy Beginnings toolkit is a good place to start.

SCOTT BEICHNER, D.O., is a pediatric hospitalist at the Cleveland Clinic Children's Hospital. He has no conflicts of interest to report.

Healthy term infants and their mothers should receive individualized care during their hospital stay, but pediatricians, obstetricians, nurses, and other health care providers should work together to determine the optimal time for hospital discharge for each mother-infant dyad, according to a policy statement issued by the American Academy of Pediatrics.

“There have been new studies since [the previous policy statement was published in 2004] to find out if there are better ways to assess the readiness for discharge of a healthy term infant, and these studies have shown that perceptions of readiness or unreadiness at the time of discharge often differ among pediatricians, obstetricians, and mothers,” said lead author Dr. Praveen Kumar, a neonatologist at Northwestern University, Chicago.

The new statement recommends that “the hospital stay of the mother and her healthy term newborn infant should be long enough to allow identification of early problems and to ensure that the family is able and prepared to care for the infant at home.”

Dr. Kumar and eight other members of the AAP's Committee on Fetus and Newborn wrote the statement, which recommends following a set of 16 minimum criteria before discharging a term newborn (Pediatrics 2010;125:405-9).

“It is our recommendation that all hospitals should develop guidelines in collaboration with appropriate community agencies and third-party payers, to establish hospital-stay and follow-up programs for healthy term infants that implement these recommendations,” Dr. Kumar said in an interview.

The statement also recommends that physicians use the AAP's Safe and Healthy Beginnings toolkit, which contains a discharge readiness checklist (http://practice.aap.org/public/Newborn_Discharge_SAMPLE.pdf

In making discharge assessments, the committee advises determining that the clinical course and physical examination of the newborn reveal no abnormalities that require additional hospitalization, vital signs are within normal ranges, and there is a history of successful feedings, urinations, and bowel movements and a lack of significant circumcisional bleeding. Other examinations should assess for the clinical risk of hyperbilirubinemia, and for sepsis based on maternal risk factors and in accord with guidelines for preventing perinatal group B streptococcal disease.

Testing of newborns' blood type as well as their cord blood should be performed as clinically indicated. Hospital protocols and state regulations may call for other metabolic and hearing screenings. The newborn should receive the initial hepatitis B vaccine according to the current immunization schedule.

Mothers should have certain blood tests performed, including screening tests for syphilis and hepatitis B surface antigen and other tests required by state regulations, such as HIV testing. Other assessments should consider the mother's knowledge, ability, and confidence to provide adequate care for her infant—including barriers to adequate follow-up care for the newborn—as well as family, environmental, and social risk factors.

“The length of stay should accommodate the unique characteristics of each mother-infant dyad, including the health of the mother, the health and stability of the infant, the ability and confidence of the mother to care for her infant, the adequacy of support systems at home, and access to appropriate follow-up care,” Dr. Kumar said. The decision to discharge a newborn should be made jointly with input from the mother, her obstetrician, and nursing staff, social workers, and other health care providers involved in the care of the mother and her infant.

Once a medical home for the newborn has been identified and a plan for timely communication of clinical information to the medical home is in place, the committee recommends making a follow-up appointment for the infant within 48 hours of discharge, but no later than 72 hours, if the infant was discharged less than 48 hours after delivery.

Disclosures: Dr. Kumar said he had no relevant disclosures to report.

My Take

Caring for the Mother-Infant Dyad

The recommendations in the American Academy of Pediatrics policy statement should be considered in the discharge management of any healthy term infant. Hopefully, many of the guidelines are being implemented already in most nurseries.

Pediatric hospitalists are in a unique position to be advocates in the care of the mother-infant dyad. Pediatric hospitalists can assess the medical needs of the infant and observe how the mother interacts with the infant. In their administrative role, pediatric hospitalists also can support quality improvement efforts related to the nursery and to the care of the mother-infant dyad.

We also need to recognize the importance of establishing the medical home for meeting the ongoing medical and social needs of the newborn and mother, and for eliminating potential barriers to adequate follow-up care.

Implementing these minimum requirements for quality care in the newborn nursery may appear challenging, but it's well worth the effort and not as arduous as it may appear. The AAP's Safe and Healthy Beginnings toolkit is a good place to start.

SCOTT BEICHNER, D.O., is a pediatric hospitalist at the Cleveland Clinic Children's Hospital. He has no conflicts of interest to report.