Jeff Evans

WASHINGTON — Strong quadriceps muscles appear to protect against cartilage loss in some parts of the knee in most people, but larger muscle mass in the leg may be associated with x-ray progression of knee osteoarthritis in women, according to findings from two studies presented at the annual meeting of the American College of Rheumatology.

Specifically, strong quadriceps muscles protected the patellofemoral joint from cartilage loss and did not worsen its loss in the tibiofemoral joint in both men and women.

A large leg muscle mass overall did not appear to influence the x-ray progression of osteoarthritis (OA) in the patellofemoral joint, except for the medial aspect of the joint in women.

Speaking during a press conference, Dr. Shreyasee Amin of the Mayo Clinic, Rochester, Minn., noted that strong quadriceps have generally been viewed as protective against knee OA. But some previous studies have found evidence that greater quadriceps strength may actually do more harm than good in the tibiofemoral joint in knees with mechanical malalignment.

But these earlier studies used x-rays to measure progression, which is an indirect measure of cartilage loss, the hallmark of OA. Pathologic changes to the meniscus on x-ray also can appear to cause an increase in joint-space narrowing, yet not reflect any real change in cartilage, she said.

Dr. Amin and her colleagues prospectively performed MRI scans at baseline, 15 months, and 30 months, and measured the quadriceps strength at baseline in a cohort of 265 men and women with symptomatic knee OA. The patients had a mean age of 67 years and a mean body mass index (BMI) of 31.5 kg/m

Upon dividing the patients into three levels of strength for each gender, the investigators found that men and women who had the greatest quadriceps strength were 60% less likely to lose cartilage in the lateral aspect of the patellofemoral joint after 30 months than were those who had the least strength.

“The quadriceps muscle could help stabilize the patella and prevent it from subluxing laterally, and so we feel that that might be a reason why greater quadriceps strength protects against cartilage loss at the lateral patellofemoral joint,” she said.

MRI scans showed no evidence that greater quadriceps strength either protected or worsened cartilage loss at other areas of the knee (the tibiofemoral joint or the medial aspect of the patellofemoral joint).

The analyses were adjusted for age, BMI, gender and baseline cartilage scores.

In a subgroup analysis of patients who had their knees measured for malalignment, varus alignment (bowleg) of 5 degrees or more did not increase the risk for tibiofemoral joint cartilage loss. There were too few people who had a valgus alignment (knock knee) of 5 degrees or more for analyses.

During a separate presentation at the same meeting, Dr. David J. Hunter of Boston University reported that a large amount of lean muscle mass in the leg had no effect on the x-ray progression of patellofemoral OA, after correcting for race, height, and total percentage of fat. But women with the largest muscle mass were more likely to experience progression of medial patellofemoral OA than were women with the least amount of leg muscle mass, even after adjusting for those confounding variables.

“I really want to emphasize that a lot of the effects that we saw with muscle mass were largely mitigated when we adjusted for total percent fat and race. The differences in prevalence [of joint space narrowing progression] were quite profound in this study, such that it was much more common in blacks, particularly in black women,” Dr. Hunter said at the meeting.

Dr. Hunter and his associates measured OA progression with weight-bearing, skyline x-rays that were taken at baseline and after 36 months in a subset of 796 patients with and without knee pain on most days of the month. The patients were originally part of a cohort of 3,075 white and black men and women aged 70–79 years in the multicenter, community-based Dynamics of Health, Aging, and Body Composition (Health ABC) study on knee OA. The investigators defined OA progression as an increase in the joint space narrowing score as observed on the radiograph.

The results could possibly be explained by an increased pull of the vastus medialis oblique muscle in patients with large muscle mass, which would pull the patella medially and increase the potential for medial patellofemoral joint space narrowing progression.

The force of knee flexion might also be increased in individuals with large leg muscle mass because of a large hamstring muscle, which could potentially increase the patellofemoral joint reaction force, Dr. Hunter proposed.

Muscle mass itself also might be a proxy for physical activity, which itself may predispose a person toward progression, he added.

WASHINGTON — Strong quadriceps muscles appear to protect against cartilage loss in some parts of the knee in most people, but larger muscle mass in the leg may be associated with x-ray progression of knee osteoarthritis in women, according to findings from two studies presented at the annual meeting of the American College of Rheumatology.

Specifically, strong quadriceps muscles protected the patellofemoral joint from cartilage loss and did not worsen its loss in the tibiofemoral joint in both men and women.

A large leg muscle mass overall did not appear to influence the x-ray progression of osteoarthritis (OA) in the patellofemoral joint, except for the medial aspect of the joint in women.

Speaking during a press conference, Dr. Shreyasee Amin of the Mayo Clinic, Rochester, Minn., noted that strong quadriceps have generally been viewed as protective against knee OA. But some previous studies have found evidence that greater quadriceps strength may actually do more harm than good in the tibiofemoral joint in knees with mechanical malalignment.

But these earlier studies used x-rays to measure progression, which is an indirect measure of cartilage loss, the hallmark of OA. Pathologic changes to the meniscus on x-ray also can appear to cause an increase in joint-space narrowing, yet not reflect any real change in cartilage, she said.

Dr. Amin and her colleagues prospectively performed MRI scans at baseline, 15 months, and 30 months, and measured the quadriceps strength at baseline in a cohort of 265 men and women with symptomatic knee OA. The patients had a mean age of 67 years and a mean body mass index (BMI) of 31.5 kg/m

Upon dividing the patients into three levels of strength for each gender, the investigators found that men and women who had the greatest quadriceps strength were 60% less likely to lose cartilage in the lateral aspect of the patellofemoral joint after 30 months than were those who had the least strength.

“The quadriceps muscle could help stabilize the patella and prevent it from subluxing laterally, and so we feel that that might be a reason why greater quadriceps strength protects against cartilage loss at the lateral patellofemoral joint,” she said.

MRI scans showed no evidence that greater quadriceps strength either protected or worsened cartilage loss at other areas of the knee (the tibiofemoral joint or the medial aspect of the patellofemoral joint).

The analyses were adjusted for age, BMI, gender and baseline cartilage scores.

In a subgroup analysis of patients who had their knees measured for malalignment, varus alignment (bowleg) of 5 degrees or more did not increase the risk for tibiofemoral joint cartilage loss. There were too few people who had a valgus alignment (knock knee) of 5 degrees or more for analyses.

During a separate presentation at the same meeting, Dr. David J. Hunter of Boston University reported that a large amount of lean muscle mass in the leg had no effect on the x-ray progression of patellofemoral OA, after correcting for race, height, and total percentage of fat. But women with the largest muscle mass were more likely to experience progression of medial patellofemoral OA than were women with the least amount of leg muscle mass, even after adjusting for those confounding variables.

“I really want to emphasize that a lot of the effects that we saw with muscle mass were largely mitigated when we adjusted for total percent fat and race. The differences in prevalence [of joint space narrowing progression] were quite profound in this study, such that it was much more common in blacks, particularly in black women,” Dr. Hunter said at the meeting.

Dr. Hunter and his associates measured OA progression with weight-bearing, skyline x-rays that were taken at baseline and after 36 months in a subset of 796 patients with and without knee pain on most days of the month. The patients were originally part of a cohort of 3,075 white and black men and women aged 70–79 years in the multicenter, community-based Dynamics of Health, Aging, and Body Composition (Health ABC) study on knee OA. The investigators defined OA progression as an increase in the joint space narrowing score as observed on the radiograph.

The results could possibly be explained by an increased pull of the vastus medialis oblique muscle in patients with large muscle mass, which would pull the patella medially and increase the potential for medial patellofemoral joint space narrowing progression.

The force of knee flexion might also be increased in individuals with large leg muscle mass because of a large hamstring muscle, which could potentially increase the patellofemoral joint reaction force, Dr. Hunter proposed.

Muscle mass itself also might be a proxy for physical activity, which itself may predispose a person toward progression, he added.

WASHINGTON — Strong quadriceps muscles appear to protect against cartilage loss in some parts of the knee in most people, but larger muscle mass in the leg may be associated with x-ray progression of knee osteoarthritis in women, according to findings from two studies presented at the annual meeting of the American College of Rheumatology.

Specifically, strong quadriceps muscles protected the patellofemoral joint from cartilage loss and did not worsen its loss in the tibiofemoral joint in both men and women.

A large leg muscle mass overall did not appear to influence the x-ray progression of osteoarthritis (OA) in the patellofemoral joint, except for the medial aspect of the joint in women.

Speaking during a press conference, Dr. Shreyasee Amin of the Mayo Clinic, Rochester, Minn., noted that strong quadriceps have generally been viewed as protective against knee OA. But some previous studies have found evidence that greater quadriceps strength may actually do more harm than good in the tibiofemoral joint in knees with mechanical malalignment.

But these earlier studies used x-rays to measure progression, which is an indirect measure of cartilage loss, the hallmark of OA. Pathologic changes to the meniscus on x-ray also can appear to cause an increase in joint-space narrowing, yet not reflect any real change in cartilage, she said.

Dr. Amin and her colleagues prospectively performed MRI scans at baseline, 15 months, and 30 months, and measured the quadriceps strength at baseline in a cohort of 265 men and women with symptomatic knee OA. The patients had a mean age of 67 years and a mean body mass index (BMI) of 31.5 kg/m

Upon dividing the patients into three levels of strength for each gender, the investigators found that men and women who had the greatest quadriceps strength were 60% less likely to lose cartilage in the lateral aspect of the patellofemoral joint after 30 months than were those who had the least strength.

“The quadriceps muscle could help stabilize the patella and prevent it from subluxing laterally, and so we feel that that might be a reason why greater quadriceps strength protects against cartilage loss at the lateral patellofemoral joint,” she said.

MRI scans showed no evidence that greater quadriceps strength either protected or worsened cartilage loss at other areas of the knee (the tibiofemoral joint or the medial aspect of the patellofemoral joint).

The analyses were adjusted for age, BMI, gender and baseline cartilage scores.

In a subgroup analysis of patients who had their knees measured for malalignment, varus alignment (bowleg) of 5 degrees or more did not increase the risk for tibiofemoral joint cartilage loss. There were too few people who had a valgus alignment (knock knee) of 5 degrees or more for analyses.

During a separate presentation at the same meeting, Dr. David J. Hunter of Boston University reported that a large amount of lean muscle mass in the leg had no effect on the x-ray progression of patellofemoral OA, after correcting for race, height, and total percentage of fat. But women with the largest muscle mass were more likely to experience progression of medial patellofemoral OA than were women with the least amount of leg muscle mass, even after adjusting for those confounding variables.

“I really want to emphasize that a lot of the effects that we saw with muscle mass were largely mitigated when we adjusted for total percent fat and race. The differences in prevalence [of joint space narrowing progression] were quite profound in this study, such that it was much more common in blacks, particularly in black women,” Dr. Hunter said at the meeting.

Dr. Hunter and his associates measured OA progression with weight-bearing, skyline x-rays that were taken at baseline and after 36 months in a subset of 796 patients with and without knee pain on most days of the month. The patients were originally part of a cohort of 3,075 white and black men and women aged 70–79 years in the multicenter, community-based Dynamics of Health, Aging, and Body Composition (Health ABC) study on knee OA. The investigators defined OA progression as an increase in the joint space narrowing score as observed on the radiograph.

The results could possibly be explained by an increased pull of the vastus medialis oblique muscle in patients with large muscle mass, which would pull the patella medially and increase the potential for medial patellofemoral joint space narrowing progression.

The force of knee flexion might also be increased in individuals with large leg muscle mass because of a large hamstring muscle, which could potentially increase the patellofemoral joint reaction force, Dr. Hunter proposed.

Muscle mass itself also might be a proxy for physical activity, which itself may predispose a person toward progression, he added.

CHICAGO — The results of prospective screening for skin lesions in patients who have Parkinson's disease have suggested that melanoma may occur at a significantly higher rate in these patients, Dr. John M. Bertoni reported at the annual meeting of the American Neurological Association.

Previous reports have suggested an association between melanoma and Parkinson's disease, but all have been retrospective. The use of levodopa has been associated with melanoma in case series, but no controlled study has been conducted, according to Dr. Bertoni, a neurologist at Creighton University, Omaha, Neb.

If the results are confirmed, Parkinson's disease patients should probably have a dermatologic evaluation, but there is no evidence to suggest how often that might be necessary, he said at his poster presentation during the meeting.

Of 2,106 patients with confirmed idiopathic Parkinson's disease who were screened prospectively for skin lesions by a dermatologist at 26 U.S. and 5 Canadian sites, 24 (1.1%) were newly diagnosed with melanoma, according to Dr. Bertoni. Another 3.4% of the patients had a history of prior melanoma.

In comparison with prevalence statistics available from the National Cancer Institute's Surveillance, Epidemiology, and End Results registry during 1997–2001, Parkinson's disease patients were 2.2 times as likely to have melanoma as were individuals in the general U.S. population.

Parkinson's disease patients had an age-adjusted relative risk for melanoma that was 10.6 times higher than that of individuals who participated in the voluntary, free skin cancer screening programs that were sponsored by the American Academy of Dermatology during 1985–1999, he said. After adjustment for gender alone, melanoma was 8.3 times more likely to occur in patients with Parkinson's disease than in AAD screening program participants.

In Dr. Bertoni's current study, melanoma was significantly associated with more severe Parkinson's disease, older age, and the presence of a greater number of risk factors for melanoma. Most patients (85%) were currently using or had used levodopa, but use of the drug, or any other dopaminergic agent, was not significantly associated with an increased incidence of melanoma.

There are no clear reasons for what might be driving an increased risk of melanoma in Parkinson's disease patients, Dr. Bertoni said.

CHICAGO — The results of prospective screening for skin lesions in patients who have Parkinson's disease have suggested that melanoma may occur at a significantly higher rate in these patients, Dr. John M. Bertoni reported at the annual meeting of the American Neurological Association.

Previous reports have suggested an association between melanoma and Parkinson's disease, but all have been retrospective. The use of levodopa has been associated with melanoma in case series, but no controlled study has been conducted, according to Dr. Bertoni, a neurologist at Creighton University, Omaha, Neb.

If the results are confirmed, Parkinson's disease patients should probably have a dermatologic evaluation, but there is no evidence to suggest how often that might be necessary, he said at his poster presentation during the meeting.

Of 2,106 patients with confirmed idiopathic Parkinson's disease who were screened prospectively for skin lesions by a dermatologist at 26 U.S. and 5 Canadian sites, 24 (1.1%) were newly diagnosed with melanoma, according to Dr. Bertoni. Another 3.4% of the patients had a history of prior melanoma.

In comparison with prevalence statistics available from the National Cancer Institute's Surveillance, Epidemiology, and End Results registry during 1997–2001, Parkinson's disease patients were 2.2 times as likely to have melanoma as were individuals in the general U.S. population.

Parkinson's disease patients had an age-adjusted relative risk for melanoma that was 10.6 times higher than that of individuals who participated in the voluntary, free skin cancer screening programs that were sponsored by the American Academy of Dermatology during 1985–1999, he said. After adjustment for gender alone, melanoma was 8.3 times more likely to occur in patients with Parkinson's disease than in AAD screening program participants.

In Dr. Bertoni's current study, melanoma was significantly associated with more severe Parkinson's disease, older age, and the presence of a greater number of risk factors for melanoma. Most patients (85%) were currently using or had used levodopa, but use of the drug, or any other dopaminergic agent, was not significantly associated with an increased incidence of melanoma.

There are no clear reasons for what might be driving an increased risk of melanoma in Parkinson's disease patients, Dr. Bertoni said.

CHICAGO — The results of prospective screening for skin lesions in patients who have Parkinson's disease have suggested that melanoma may occur at a significantly higher rate in these patients, Dr. John M. Bertoni reported at the annual meeting of the American Neurological Association.

Previous reports have suggested an association between melanoma and Parkinson's disease, but all have been retrospective. The use of levodopa has been associated with melanoma in case series, but no controlled study has been conducted, according to Dr. Bertoni, a neurologist at Creighton University, Omaha, Neb.

If the results are confirmed, Parkinson's disease patients should probably have a dermatologic evaluation, but there is no evidence to suggest how often that might be necessary, he said at his poster presentation during the meeting.

Of 2,106 patients with confirmed idiopathic Parkinson's disease who were screened prospectively for skin lesions by a dermatologist at 26 U.S. and 5 Canadian sites, 24 (1.1%) were newly diagnosed with melanoma, according to Dr. Bertoni. Another 3.4% of the patients had a history of prior melanoma.

In comparison with prevalence statistics available from the National Cancer Institute's Surveillance, Epidemiology, and End Results registry during 1997–2001, Parkinson's disease patients were 2.2 times as likely to have melanoma as were individuals in the general U.S. population.

Parkinson's disease patients had an age-adjusted relative risk for melanoma that was 10.6 times higher than that of individuals who participated in the voluntary, free skin cancer screening programs that were sponsored by the American Academy of Dermatology during 1985–1999, he said. After adjustment for gender alone, melanoma was 8.3 times more likely to occur in patients with Parkinson's disease than in AAD screening program participants.

In Dr. Bertoni's current study, melanoma was significantly associated with more severe Parkinson's disease, older age, and the presence of a greater number of risk factors for melanoma. Most patients (85%) were currently using or had used levodopa, but use of the drug, or any other dopaminergic agent, was not significantly associated with an increased incidence of melanoma.

There are no clear reasons for what might be driving an increased risk of melanoma in Parkinson's disease patients, Dr. Bertoni said.

CHICAGO — Ongoing clinical trials for two implanted devices designed to interrupt or predict seizures herald an area of clinical research that has quickly gained ground during the last 5 years, Dr. Brian Litt said at the annual meeting of the American Neurological Association.

Research into seizure prediction, most of which has occurred in the past 15 years, has been “very controversial,” mostly because of people getting too excited about findings very early on, said Dr. Litt, of the departments of neurology and bioengineering at the University of Pennsylvania, Philadelphia.

Early studies were plagued by overreliance on abstract functions rather than on clinical physiological parameters, and they lacked statistical rigor.

As a result, the databases were biased toward seizures because much of the data were taken from inpatients who had many seizures during hospital stays.

“Those data are not what it's like to live with epilepsy; you might have one seizure a month, you might have four a month. But clearly the preponderance of the data is interictal,” he said.

A data set heavily enriched with seizures makes it much more likely that attempts to predict seizures at broad intervals will, in fact, detect a seizure. This made it impossible to reproduce the claims of seizure prediction that were announced in early studies.

“We also found that listening to patients was really important,” Dr. Litt said, because many patients tell their physicians that sometimes hours or days before a seizure onset, they have a feeling—or prodrome—that tells them they are likely to have a seizure. And the patients may or may not have a seizure.

“The model [for predicting seizures] has to account for this,” he said.

These lessons taught Dr. Litt and his colleagues that they were very unlikely to predict an exact seizure, but that it was likely they could identify periods of time in which the probability of a seizure's occurring is greatly increased.

No efficacy data are yet available for the two devices that are being tested in phase III trials, but no adverse events have occurred.

In Medtronic Inc.'s Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTE) trial, about 150 adult patients with medically refractory partial-onset epilepsy will receive the Intercept Epilepsy Control System. The implanted device, which bilaterally stimulates the anterior nucleus of the thalamus but does not sense or respond to EEG activity, will be turned on in some patients but not in others during the trial's double-blind phase. Medtronic decided to continue the SANTE trial after it recently passed its midterm analysis, according to Dr. Litt.

The Responsive Neurostimulator (RNS) system from NeuroPace Inc. will be tested in about 240 adult patients to determine if it can reduce the frequency of medically uncontrolled and disabling partial-onset seizures. All patients will be implanted with the device, which scans EEG recordings for particular patterns associated with seizure onset or impending seizures, and then stimulates epileptogenic foci through intracranial electrodes.

In a safety study of about 50 patients with more than four seizures per month who were implanted with the RNS device, 43% of those with complex partial seizures and 35% of those with disabling motor seizures had a 50% or greater reduction in seizures, Dr. Litt said.

“Is this a home run? No. Does it mean that it's effective? No. Does it mean that there's proof of principle enough to perhaps go forward? I think it does,” Dr. Litt said.

“Remember, this is a first-generation device. Judge this as a work in progress, like the first pacemaker,” he added.

Dr. Litt has contributed patents through the University of Pennsylvania for NeuroPace's RNS device.

He is a consultant to BioNeuronics Corp., and he helped to found BioQuantix Corp. through the University of Pennsylvania.

Major questions still remain in understanding and mapping epileptic networks in the brain, such as where to place electrodes, where to sense seizure onset, and where to stimulate the brain. Researchers also want to know how seizures are generated over time.

To answer these questions, Dr. Litt and his associates have examined seizures in patients with RNS devices, which save about a minute of data prior to stimulation and also for a short period afterward.

Analyses of the 2-second period before a seizure began in thousands of events distinguished between effective and ineffective types of stimulation. For particular stereotyped seizure onsets, the researchers used specific characteristics of synchrony, frequency of activity, and the relationship between the stimulus and the seizure waveform to determine if stimulation would be effective or not.

“The bottom line is that seizures in which stimulation is not effective are ones that are likely more evolved or perhaps began in a different place in the network and spread to these regions before the stimulation occurred,” he said.

Although Dr. Litt's model for seizure generation has not been statistically proven, his group's research suggests that seizures “may occur in a reproducible cascade of events” in which there are periods of increased complex epileptiform activity in the hours or days before a seizure, followed in the 2 hours before the seizure by short seizurelike bursts of activity, or “seizlets,” that last 1–5 seconds. These seizlets appear to build exponentially as the seizure approaches and activity ramps up.

To prove that this cascade of events exists, the investigators have built detectors that can quantitatively detect seizures in large chunks of data. When seizure and nonseizure events are mixed up and randomized, the two events can be distinguished with a certain latency, which increases as the likelihood of correctly predicting a seizure event increases.

Other collaborators with Dr. Litt may have come across a good method for validating the performance of algorithms that are designed to predict seizures. This method also may have discovered the first evidence for the EEG patterns of a definitive preictal period (J. Neurophysiol. 2006 Oct. 4 [Epub DOI:10.1152/jn.00190.2006]).

Pinpointing the location of seizures has benefited from research using high-frequency EEG. High-frequency EEG readings were not recognized as clinically significant until recent studies showed that the characteristic waveform flattening, or “electro-decrement,” of intracranial EEG before a seizure is actually high-frequency activity that was filtered out by intracranial EEGs that were calibrated to filter settings of pen and paper EEG machines from the 1950s, Dr. Litt said.

For many seizures, a rise in high-frequency epileptiform oscillations can indicate an impending seizure 40 minutes in advance (Brain 2004;127:1496–506).

Investigations of the density of these high-frequency epileptiform oscillations during a period of time around specific electrodes in the brain have helped to map the distribution of nodes that are “heating up” before seizure onset. These maps have suggested that the focal point of a seizure is not really like a single point, as was previously thought, but is “more like a cloud.

It's areas that are buzzing and trying to initiate synchrony that seem to be going from one place to the other to generate the seizure, and which ones actually start the seizure may vary,” Dr. Litt said.

CHICAGO — Ongoing clinical trials for two implanted devices designed to interrupt or predict seizures herald an area of clinical research that has quickly gained ground during the last 5 years, Dr. Brian Litt said at the annual meeting of the American Neurological Association.

Research into seizure prediction, most of which has occurred in the past 15 years, has been “very controversial,” mostly because of people getting too excited about findings very early on, said Dr. Litt, of the departments of neurology and bioengineering at the University of Pennsylvania, Philadelphia.

Early studies were plagued by overreliance on abstract functions rather than on clinical physiological parameters, and they lacked statistical rigor.

As a result, the databases were biased toward seizures because much of the data were taken from inpatients who had many seizures during hospital stays.

“Those data are not what it's like to live with epilepsy; you might have one seizure a month, you might have four a month. But clearly the preponderance of the data is interictal,” he said.

A data set heavily enriched with seizures makes it much more likely that attempts to predict seizures at broad intervals will, in fact, detect a seizure. This made it impossible to reproduce the claims of seizure prediction that were announced in early studies.

“We also found that listening to patients was really important,” Dr. Litt said, because many patients tell their physicians that sometimes hours or days before a seizure onset, they have a feeling—or prodrome—that tells them they are likely to have a seizure. And the patients may or may not have a seizure.

“The model [for predicting seizures] has to account for this,” he said.

These lessons taught Dr. Litt and his colleagues that they were very unlikely to predict an exact seizure, but that it was likely they could identify periods of time in which the probability of a seizure's occurring is greatly increased.

No efficacy data are yet available for the two devices that are being tested in phase III trials, but no adverse events have occurred.

In Medtronic Inc.'s Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTE) trial, about 150 adult patients with medically refractory partial-onset epilepsy will receive the Intercept Epilepsy Control System. The implanted device, which bilaterally stimulates the anterior nucleus of the thalamus but does not sense or respond to EEG activity, will be turned on in some patients but not in others during the trial's double-blind phase. Medtronic decided to continue the SANTE trial after it recently passed its midterm analysis, according to Dr. Litt.

The Responsive Neurostimulator (RNS) system from NeuroPace Inc. will be tested in about 240 adult patients to determine if it can reduce the frequency of medically uncontrolled and disabling partial-onset seizures. All patients will be implanted with the device, which scans EEG recordings for particular patterns associated with seizure onset or impending seizures, and then stimulates epileptogenic foci through intracranial electrodes.

In a safety study of about 50 patients with more than four seizures per month who were implanted with the RNS device, 43% of those with complex partial seizures and 35% of those with disabling motor seizures had a 50% or greater reduction in seizures, Dr. Litt said.

“Is this a home run? No. Does it mean that it's effective? No. Does it mean that there's proof of principle enough to perhaps go forward? I think it does,” Dr. Litt said.

“Remember, this is a first-generation device. Judge this as a work in progress, like the first pacemaker,” he added.

Dr. Litt has contributed patents through the University of Pennsylvania for NeuroPace's RNS device.

He is a consultant to BioNeuronics Corp., and he helped to found BioQuantix Corp. through the University of Pennsylvania.

Major questions still remain in understanding and mapping epileptic networks in the brain, such as where to place electrodes, where to sense seizure onset, and where to stimulate the brain. Researchers also want to know how seizures are generated over time.

To answer these questions, Dr. Litt and his associates have examined seizures in patients with RNS devices, which save about a minute of data prior to stimulation and also for a short period afterward.

Analyses of the 2-second period before a seizure began in thousands of events distinguished between effective and ineffective types of stimulation. For particular stereotyped seizure onsets, the researchers used specific characteristics of synchrony, frequency of activity, and the relationship between the stimulus and the seizure waveform to determine if stimulation would be effective or not.

“The bottom line is that seizures in which stimulation is not effective are ones that are likely more evolved or perhaps began in a different place in the network and spread to these regions before the stimulation occurred,” he said.

Although Dr. Litt's model for seizure generation has not been statistically proven, his group's research suggests that seizures “may occur in a reproducible cascade of events” in which there are periods of increased complex epileptiform activity in the hours or days before a seizure, followed in the 2 hours before the seizure by short seizurelike bursts of activity, or “seizlets,” that last 1–5 seconds. These seizlets appear to build exponentially as the seizure approaches and activity ramps up.

To prove that this cascade of events exists, the investigators have built detectors that can quantitatively detect seizures in large chunks of data. When seizure and nonseizure events are mixed up and randomized, the two events can be distinguished with a certain latency, which increases as the likelihood of correctly predicting a seizure event increases.

Other collaborators with Dr. Litt may have come across a good method for validating the performance of algorithms that are designed to predict seizures. This method also may have discovered the first evidence for the EEG patterns of a definitive preictal period (J. Neurophysiol. 2006 Oct. 4 [Epub DOI:10.1152/jn.00190.2006]).

Pinpointing the location of seizures has benefited from research using high-frequency EEG. High-frequency EEG readings were not recognized as clinically significant until recent studies showed that the characteristic waveform flattening, or “electro-decrement,” of intracranial EEG before a seizure is actually high-frequency activity that was filtered out by intracranial EEGs that were calibrated to filter settings of pen and paper EEG machines from the 1950s, Dr. Litt said.

For many seizures, a rise in high-frequency epileptiform oscillations can indicate an impending seizure 40 minutes in advance (Brain 2004;127:1496–506).

Investigations of the density of these high-frequency epileptiform oscillations during a period of time around specific electrodes in the brain have helped to map the distribution of nodes that are “heating up” before seizure onset. These maps have suggested that the focal point of a seizure is not really like a single point, as was previously thought, but is “more like a cloud.

It's areas that are buzzing and trying to initiate synchrony that seem to be going from one place to the other to generate the seizure, and which ones actually start the seizure may vary,” Dr. Litt said.

CHICAGO — Ongoing clinical trials for two implanted devices designed to interrupt or predict seizures herald an area of clinical research that has quickly gained ground during the last 5 years, Dr. Brian Litt said at the annual meeting of the American Neurological Association.

Research into seizure prediction, most of which has occurred in the past 15 years, has been “very controversial,” mostly because of people getting too excited about findings very early on, said Dr. Litt, of the departments of neurology and bioengineering at the University of Pennsylvania, Philadelphia.

Early studies were plagued by overreliance on abstract functions rather than on clinical physiological parameters, and they lacked statistical rigor.

As a result, the databases were biased toward seizures because much of the data were taken from inpatients who had many seizures during hospital stays.

“Those data are not what it's like to live with epilepsy; you might have one seizure a month, you might have four a month. But clearly the preponderance of the data is interictal,” he said.

A data set heavily enriched with seizures makes it much more likely that attempts to predict seizures at broad intervals will, in fact, detect a seizure. This made it impossible to reproduce the claims of seizure prediction that were announced in early studies.

“We also found that listening to patients was really important,” Dr. Litt said, because many patients tell their physicians that sometimes hours or days before a seizure onset, they have a feeling—or prodrome—that tells them they are likely to have a seizure. And the patients may or may not have a seizure.

“The model [for predicting seizures] has to account for this,” he said.

These lessons taught Dr. Litt and his colleagues that they were very unlikely to predict an exact seizure, but that it was likely they could identify periods of time in which the probability of a seizure's occurring is greatly increased.

No efficacy data are yet available for the two devices that are being tested in phase III trials, but no adverse events have occurred.

In Medtronic Inc.'s Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTE) trial, about 150 adult patients with medically refractory partial-onset epilepsy will receive the Intercept Epilepsy Control System. The implanted device, which bilaterally stimulates the anterior nucleus of the thalamus but does not sense or respond to EEG activity, will be turned on in some patients but not in others during the trial's double-blind phase. Medtronic decided to continue the SANTE trial after it recently passed its midterm analysis, according to Dr. Litt.

The Responsive Neurostimulator (RNS) system from NeuroPace Inc. will be tested in about 240 adult patients to determine if it can reduce the frequency of medically uncontrolled and disabling partial-onset seizures. All patients will be implanted with the device, which scans EEG recordings for particular patterns associated with seizure onset or impending seizures, and then stimulates epileptogenic foci through intracranial electrodes.

In a safety study of about 50 patients with more than four seizures per month who were implanted with the RNS device, 43% of those with complex partial seizures and 35% of those with disabling motor seizures had a 50% or greater reduction in seizures, Dr. Litt said.

“Is this a home run? No. Does it mean that it's effective? No. Does it mean that there's proof of principle enough to perhaps go forward? I think it does,” Dr. Litt said.

“Remember, this is a first-generation device. Judge this as a work in progress, like the first pacemaker,” he added.

Dr. Litt has contributed patents through the University of Pennsylvania for NeuroPace's RNS device.

He is a consultant to BioNeuronics Corp., and he helped to found BioQuantix Corp. through the University of Pennsylvania.

Major questions still remain in understanding and mapping epileptic networks in the brain, such as where to place electrodes, where to sense seizure onset, and where to stimulate the brain. Researchers also want to know how seizures are generated over time.

To answer these questions, Dr. Litt and his associates have examined seizures in patients with RNS devices, which save about a minute of data prior to stimulation and also for a short period afterward.

Analyses of the 2-second period before a seizure began in thousands of events distinguished between effective and ineffective types of stimulation. For particular stereotyped seizure onsets, the researchers used specific characteristics of synchrony, frequency of activity, and the relationship between the stimulus and the seizure waveform to determine if stimulation would be effective or not.

“The bottom line is that seizures in which stimulation is not effective are ones that are likely more evolved or perhaps began in a different place in the network and spread to these regions before the stimulation occurred,” he said.

Although Dr. Litt's model for seizure generation has not been statistically proven, his group's research suggests that seizures “may occur in a reproducible cascade of events” in which there are periods of increased complex epileptiform activity in the hours or days before a seizure, followed in the 2 hours before the seizure by short seizurelike bursts of activity, or “seizlets,” that last 1–5 seconds. These seizlets appear to build exponentially as the seizure approaches and activity ramps up.

To prove that this cascade of events exists, the investigators have built detectors that can quantitatively detect seizures in large chunks of data. When seizure and nonseizure events are mixed up and randomized, the two events can be distinguished with a certain latency, which increases as the likelihood of correctly predicting a seizure event increases.

Other collaborators with Dr. Litt may have come across a good method for validating the performance of algorithms that are designed to predict seizures. This method also may have discovered the first evidence for the EEG patterns of a definitive preictal period (J. Neurophysiol. 2006 Oct. 4 [Epub DOI:10.1152/jn.00190.2006]).

Pinpointing the location of seizures has benefited from research using high-frequency EEG. High-frequency EEG readings were not recognized as clinically significant until recent studies showed that the characteristic waveform flattening, or “electro-decrement,” of intracranial EEG before a seizure is actually high-frequency activity that was filtered out by intracranial EEGs that were calibrated to filter settings of pen and paper EEG machines from the 1950s, Dr. Litt said.

For many seizures, a rise in high-frequency epileptiform oscillations can indicate an impending seizure 40 minutes in advance (Brain 2004;127:1496–506).

Investigations of the density of these high-frequency epileptiform oscillations during a period of time around specific electrodes in the brain have helped to map the distribution of nodes that are “heating up” before seizure onset. These maps have suggested that the focal point of a seizure is not really like a single point, as was previously thought, but is “more like a cloud.

It's areas that are buzzing and trying to initiate synchrony that seem to be going from one place to the other to generate the seizure, and which ones actually start the seizure may vary,” Dr. Litt said.

WASHINGTON — Strong quadriceps muscles appear to protect against cartilage loss in some parts of the knee in most people, but larger muscle mass in the knee may be associated with x-ray progression of knee osteoarthritis in women, according to findings from two studies presented at the annual meeting of the American College of Rheumatology.

Specifically, strong quadriceps muscles protected the patellofemoral joint from cartilage loss and did not worsen its loss in the tibiofemoral joint in both men and women. A large leg muscle mass overall did not appear to influence the x-ray progression of osteoarthritis (OA) in the patellofemoral joint, except for the medial aspect of the joint in women.

Speaking during a press conference, Dr. Shreyasee Amin of the Mayo Clinic, Rochester, Minn., noted that strong quadriceps have generally been viewed as protective against knee OA. But some previous studies have found evidence that greater quadriceps strength may actually do more harm than good in the tibiofemoral joint in knees with mechanical malalignment.

But these earlier studies used x-rays to measure progression, which is an indirect measure of cartilage loss, the hallmark of OA. Pathologic changes to the meniscus on x-ray also can appear to cause an increase in joint-space narrowing, yet not reflect any real change in cartilage, she said.

Dr. Amin and colleagues prospectively performed MRI scans at baseline, 15 months, and 30 months, and measured the quadriceps strength at baseline in a cohort of 265 men and women with symptomatic knee OA. The patients had a mean age of 67 years and a mean body mass index (BMI) of 31.5 kg/m

“The quadriceps muscle could help stabilize the patella and prevent it from subluxing laterally, and so we feel that that might be a reason why greater quadriceps strength protects against cartilage loss at the lateral patellofemoral joint,” she said.

MRI scans showed no evidence that greater quadriceps strength either protected or worsened cartilage loss at other areas of the knee. The analyses were adjusted for age, BMI, gender, and baseline cartilage scores.

In a subgroup analysis of patients who had their knees measured for malalignment, varus alignment (bow leg) of 5 degrees or more did not increase the risk for tibiofemoral joint cartilage loss. There were too few people who had a valgus alignment (knock knee) of 5 degrees or more for analysis.

During a separate presentation at the same meeting, Dr. David J. Hunter of Boston University reported that a large amount of lean muscle mass in the leg had no effect on the x-ray progression of patellofemoral OA, after correcting for race, height, and total percentage of fat. But women with the largest muscle mass were more likely to experience progression of medial patellofemoral OA than were women with the least amount of leg muscle mass, even after adjusting for those confounding variables.

“I really want to emphasize that a lot of the effects that we saw with muscle mass were largely mitigated when we adjusted for total percent fat and race. The differences in prevalence [of joint space narrowing progression] were quite profound in this study, such that it was much more common in blacks, particularly in black women,” Dr. Hunter said.

Dr. Hunter and his associates measured OA progression with weight-bearing, skyline x-rays that were taken at baseline and after 36 months in a subset of 796 patients with and without knee pain on most days of the month. The patients were originally part of a cohort of 3,075 white and black men and women aged 70–79 years in the multicenter, community-based Dynamics of Health, Aging, and Body Composition (Health ABC) study on knee OA.

The results could possibly be explained by an increased pull of the vastus medialis oblique muscle in patients with large muscle mass, which would pull the patella medially and increase the potential for medial patellofemoral joint space narrowing progression. The force of knee flexion might also be increased in people with large leg muscle mass because of a large hamstring muscle, which could potentially increase the patellofemoral joint reaction force. Muscle mass itself also might be a proxy for physical activity, which itself may predispose a person toward progression, according to Dr. Hunter.

WASHINGTON — Strong quadriceps muscles appear to protect against cartilage loss in some parts of the knee in most people, but larger muscle mass in the knee may be associated with x-ray progression of knee osteoarthritis in women, according to findings from two studies presented at the annual meeting of the American College of Rheumatology.

Specifically, strong quadriceps muscles protected the patellofemoral joint from cartilage loss and did not worsen its loss in the tibiofemoral joint in both men and women. A large leg muscle mass overall did not appear to influence the x-ray progression of osteoarthritis (OA) in the patellofemoral joint, except for the medial aspect of the joint in women.

Speaking during a press conference, Dr. Shreyasee Amin of the Mayo Clinic, Rochester, Minn., noted that strong quadriceps have generally been viewed as protective against knee OA. But some previous studies have found evidence that greater quadriceps strength may actually do more harm than good in the tibiofemoral joint in knees with mechanical malalignment.

But these earlier studies used x-rays to measure progression, which is an indirect measure of cartilage loss, the hallmark of OA. Pathologic changes to the meniscus on x-ray also can appear to cause an increase in joint-space narrowing, yet not reflect any real change in cartilage, she said.

Dr. Amin and colleagues prospectively performed MRI scans at baseline, 15 months, and 30 months, and measured the quadriceps strength at baseline in a cohort of 265 men and women with symptomatic knee OA. The patients had a mean age of 67 years and a mean body mass index (BMI) of 31.5 kg/m

“The quadriceps muscle could help stabilize the patella and prevent it from subluxing laterally, and so we feel that that might be a reason why greater quadriceps strength protects against cartilage loss at the lateral patellofemoral joint,” she said.

MRI scans showed no evidence that greater quadriceps strength either protected or worsened cartilage loss at other areas of the knee. The analyses were adjusted for age, BMI, gender, and baseline cartilage scores.

In a subgroup analysis of patients who had their knees measured for malalignment, varus alignment (bow leg) of 5 degrees or more did not increase the risk for tibiofemoral joint cartilage loss. There were too few people who had a valgus alignment (knock knee) of 5 degrees or more for analysis.

During a separate presentation at the same meeting, Dr. David J. Hunter of Boston University reported that a large amount of lean muscle mass in the leg had no effect on the x-ray progression of patellofemoral OA, after correcting for race, height, and total percentage of fat. But women with the largest muscle mass were more likely to experience progression of medial patellofemoral OA than were women with the least amount of leg muscle mass, even after adjusting for those confounding variables.

“I really want to emphasize that a lot of the effects that we saw with muscle mass were largely mitigated when we adjusted for total percent fat and race. The differences in prevalence [of joint space narrowing progression] were quite profound in this study, such that it was much more common in blacks, particularly in black women,” Dr. Hunter said.

Dr. Hunter and his associates measured OA progression with weight-bearing, skyline x-rays that were taken at baseline and after 36 months in a subset of 796 patients with and without knee pain on most days of the month. The patients were originally part of a cohort of 3,075 white and black men and women aged 70–79 years in the multicenter, community-based Dynamics of Health, Aging, and Body Composition (Health ABC) study on knee OA.

The results could possibly be explained by an increased pull of the vastus medialis oblique muscle in patients with large muscle mass, which would pull the patella medially and increase the potential for medial patellofemoral joint space narrowing progression. The force of knee flexion might also be increased in people with large leg muscle mass because of a large hamstring muscle, which could potentially increase the patellofemoral joint reaction force. Muscle mass itself also might be a proxy for physical activity, which itself may predispose a person toward progression, according to Dr. Hunter.

WASHINGTON — Strong quadriceps muscles appear to protect against cartilage loss in some parts of the knee in most people, but larger muscle mass in the knee may be associated with x-ray progression of knee osteoarthritis in women, according to findings from two studies presented at the annual meeting of the American College of Rheumatology.

Specifically, strong quadriceps muscles protected the patellofemoral joint from cartilage loss and did not worsen its loss in the tibiofemoral joint in both men and women. A large leg muscle mass overall did not appear to influence the x-ray progression of osteoarthritis (OA) in the patellofemoral joint, except for the medial aspect of the joint in women.

Speaking during a press conference, Dr. Shreyasee Amin of the Mayo Clinic, Rochester, Minn., noted that strong quadriceps have generally been viewed as protective against knee OA. But some previous studies have found evidence that greater quadriceps strength may actually do more harm than good in the tibiofemoral joint in knees with mechanical malalignment.

But these earlier studies used x-rays to measure progression, which is an indirect measure of cartilage loss, the hallmark of OA. Pathologic changes to the meniscus on x-ray also can appear to cause an increase in joint-space narrowing, yet not reflect any real change in cartilage, she said.

Dr. Amin and colleagues prospectively performed MRI scans at baseline, 15 months, and 30 months, and measured the quadriceps strength at baseline in a cohort of 265 men and women with symptomatic knee OA. The patients had a mean age of 67 years and a mean body mass index (BMI) of 31.5 kg/m

“The quadriceps muscle could help stabilize the patella and prevent it from subluxing laterally, and so we feel that that might be a reason why greater quadriceps strength protects against cartilage loss at the lateral patellofemoral joint,” she said.

MRI scans showed no evidence that greater quadriceps strength either protected or worsened cartilage loss at other areas of the knee. The analyses were adjusted for age, BMI, gender, and baseline cartilage scores.

In a subgroup analysis of patients who had their knees measured for malalignment, varus alignment (bow leg) of 5 degrees or more did not increase the risk for tibiofemoral joint cartilage loss. There were too few people who had a valgus alignment (knock knee) of 5 degrees or more for analysis.

During a separate presentation at the same meeting, Dr. David J. Hunter of Boston University reported that a large amount of lean muscle mass in the leg had no effect on the x-ray progression of patellofemoral OA, after correcting for race, height, and total percentage of fat. But women with the largest muscle mass were more likely to experience progression of medial patellofemoral OA than were women with the least amount of leg muscle mass, even after adjusting for those confounding variables.

“I really want to emphasize that a lot of the effects that we saw with muscle mass were largely mitigated when we adjusted for total percent fat and race. The differences in prevalence [of joint space narrowing progression] were quite profound in this study, such that it was much more common in blacks, particularly in black women,” Dr. Hunter said.

Dr. Hunter and his associates measured OA progression with weight-bearing, skyline x-rays that were taken at baseline and after 36 months in a subset of 796 patients with and without knee pain on most days of the month. The patients were originally part of a cohort of 3,075 white and black men and women aged 70–79 years in the multicenter, community-based Dynamics of Health, Aging, and Body Composition (Health ABC) study on knee OA.

The results could possibly be explained by an increased pull of the vastus medialis oblique muscle in patients with large muscle mass, which would pull the patella medially and increase the potential for medial patellofemoral joint space narrowing progression. The force of knee flexion might also be increased in people with large leg muscle mass because of a large hamstring muscle, which could potentially increase the patellofemoral joint reaction force. Muscle mass itself also might be a proxy for physical activity, which itself may predispose a person toward progression, according to Dr. Hunter.

WASHINGTON — Elevated expression of matrix metalloproteinase-3 in patients with ankylosing spondylitis may independently predict radiographic disease progression, Dr. Walter P. Maksymowych reported at the annual meeting of the American College of Rheumatology.

Joint and bone damage progression in ankylosing spondylitis becomes evident radiographically over a very long period and further damage can only be predicted from damage already visible on radiographs, making it difficult to diagnose and predict the disease course, said Dr. Maksymowych of the University of Alberta, Edmonton (Arthritis Rheum. 2004;50:2622–32).

This is “perhaps one of the greatest challenges in the field of spondylitis research,” he said. The dependence on radiographic evidence of progression poses major difficulties in “the design of clinical trials of agents that evaluate disease modification.”

Matrix metalloproteinase-3 (MMP3) was the only independent and significant biomarker to predict progression in a panel of nine serologic proteins involved in disease activity and structural damage progression in inflammatory forms of arthritis, as well as osteoclast regulation.

Dr. Maksymowych and his colleagues analyzed the proteins in 100 patients with ankylosing spondylitis in the OASIS (Outcome in Ankylosing Spondylitis International Study) longitudinal cohort that began in 1996 at four centers in the Netherlands, Belgium, and France. The patients had a mean age of 43 years and a mean disease duration of 10.6 years.

The level of MMP3 was the only biomarker that was significantly associated with the progression of structural damage at 2 years, after adjustment for age, sex, disease duration, C-reactive protein levels, and modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) at baseline. A cutoff level of 68 ng/mL MMP3 in serum and a cutoff score of 10 units on the mSASSS predicted progression at 2 years.

Radiographic progression was 78 times more likely to occur with an MMP3 level of at least 68 ng/mL and an mSASSS of at least 10 units or more than with a lower MMP3 level and a lower damage score. Overall, 15% of the patients fell into that high-risk category. Of those who developed radiographic progression by 2 years, 67% had a high MMP3 level and a high damage score.

“Neither MMP3 nor baseline mSASSS alone are of prognostic value in individual patients. However, the combination of a high MMP3 and a high baseline mSASSS score, as defined by those cutoffs, is of prognostic value in individual patients,” Dr. Maksymowych said. The next step is to test these cutoffs in another cohort of ankylosing spondylitis patients.

WASHINGTON — Elevated expression of matrix metalloproteinase-3 in patients with ankylosing spondylitis may independently predict radiographic disease progression, Dr. Walter P. Maksymowych reported at the annual meeting of the American College of Rheumatology.

Joint and bone damage progression in ankylosing spondylitis becomes evident radiographically over a very long period and further damage can only be predicted from damage already visible on radiographs, making it difficult to diagnose and predict the disease course, said Dr. Maksymowych of the University of Alberta, Edmonton (Arthritis Rheum. 2004;50:2622–32).

This is “perhaps one of the greatest challenges in the field of spondylitis research,” he said. The dependence on radiographic evidence of progression poses major difficulties in “the design of clinical trials of agents that evaluate disease modification.”

Matrix metalloproteinase-3 (MMP3) was the only independent and significant biomarker to predict progression in a panel of nine serologic proteins involved in disease activity and structural damage progression in inflammatory forms of arthritis, as well as osteoclast regulation.

Dr. Maksymowych and his colleagues analyzed the proteins in 100 patients with ankylosing spondylitis in the OASIS (Outcome in Ankylosing Spondylitis International Study) longitudinal cohort that began in 1996 at four centers in the Netherlands, Belgium, and France. The patients had a mean age of 43 years and a mean disease duration of 10.6 years.

The level of MMP3 was the only biomarker that was significantly associated with the progression of structural damage at 2 years, after adjustment for age, sex, disease duration, C-reactive protein levels, and modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) at baseline. A cutoff level of 68 ng/mL MMP3 in serum and a cutoff score of 10 units on the mSASSS predicted progression at 2 years.

Radiographic progression was 78 times more likely to occur with an MMP3 level of at least 68 ng/mL and an mSASSS of at least 10 units or more than with a lower MMP3 level and a lower damage score. Overall, 15% of the patients fell into that high-risk category. Of those who developed radiographic progression by 2 years, 67% had a high MMP3 level and a high damage score.

“Neither MMP3 nor baseline mSASSS alone are of prognostic value in individual patients. However, the combination of a high MMP3 and a high baseline mSASSS score, as defined by those cutoffs, is of prognostic value in individual patients,” Dr. Maksymowych said. The next step is to test these cutoffs in another cohort of ankylosing spondylitis patients.

WASHINGTON — Elevated expression of matrix metalloproteinase-3 in patients with ankylosing spondylitis may independently predict radiographic disease progression, Dr. Walter P. Maksymowych reported at the annual meeting of the American College of Rheumatology.

Joint and bone damage progression in ankylosing spondylitis becomes evident radiographically over a very long period and further damage can only be predicted from damage already visible on radiographs, making it difficult to diagnose and predict the disease course, said Dr. Maksymowych of the University of Alberta, Edmonton (Arthritis Rheum. 2004;50:2622–32).

This is “perhaps one of the greatest challenges in the field of spondylitis research,” he said. The dependence on radiographic evidence of progression poses major difficulties in “the design of clinical trials of agents that evaluate disease modification.”

Matrix metalloproteinase-3 (MMP3) was the only independent and significant biomarker to predict progression in a panel of nine serologic proteins involved in disease activity and structural damage progression in inflammatory forms of arthritis, as well as osteoclast regulation.

Dr. Maksymowych and his colleagues analyzed the proteins in 100 patients with ankylosing spondylitis in the OASIS (Outcome in Ankylosing Spondylitis International Study) longitudinal cohort that began in 1996 at four centers in the Netherlands, Belgium, and France. The patients had a mean age of 43 years and a mean disease duration of 10.6 years.

The level of MMP3 was the only biomarker that was significantly associated with the progression of structural damage at 2 years, after adjustment for age, sex, disease duration, C-reactive protein levels, and modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) at baseline. A cutoff level of 68 ng/mL MMP3 in serum and a cutoff score of 10 units on the mSASSS predicted progression at 2 years.

Radiographic progression was 78 times more likely to occur with an MMP3 level of at least 68 ng/mL and an mSASSS of at least 10 units or more than with a lower MMP3 level and a lower damage score. Overall, 15% of the patients fell into that high-risk category. Of those who developed radiographic progression by 2 years, 67% had a high MMP3 level and a high damage score.

“Neither MMP3 nor baseline mSASSS alone are of prognostic value in individual patients. However, the combination of a high MMP3 and a high baseline mSASSS score, as defined by those cutoffs, is of prognostic value in individual patients,” Dr. Maksymowych said. The next step is to test these cutoffs in another cohort of ankylosing spondylitis patients.

WASHINGTON — The low-permeability version of the Gore Excluder stent graft appears to reduce the volume and diameter of abdominal aortic aneurysms at 1 year significantly more than did the older, more permeable version of the stent, according to the results of a prospective study comparing the two models.

The high rate of failure with the original Gore Excluder stent graft, in which the mean maximum abdominal aortic aneurysm (AAA) diameter increased by at least 5 mm in 36% of patients after 5 years, prompted the stent's manufacturer, W.L. Gore & Associates Inc., to add a new low-permeability layer between the device's expanded polytetrafluoroethylene layer and its reinforcing membrane, Dr. Manish Mehta said at the annual meeting of the Eastern Vascular Society.

The Food and Drug Administration approved the new device in July 2004.

In a series of 428 patients who received either the new or the old Excluder for AAA treatment during 2001–2005 at the Institute for Vascular Health and Disease at Albany (N.Y.) Medical College, Dr. Mehta and his colleagues compared the outcomes of 214 patients who had CT angiography imaging results available 1 year after the procedure.

The CT angiograms revealed that 114 consecutive patients with the low-permeability stent had significantly greater declines in mean AAA volume than 100 consecutive patients with the original type of stent (163 mL to 141 mL vs. 156 mL to 160 mL). The percentage of patients with more than a 5% drop in AAA volume also was significantly greater in patients with the new stent (52%) than in those with the old stent (6%), reported Dr. Mehta, a vascular surgeon at the institute.

Compared with recipients of the old stent graft, significantly fewer patients with the new device had more than a 5% increase in AAA volume (12% vs. 2.6%).

A significantly greater percentage of patients with the low-permeability stent had at least a 5-mm decrease in maximum AAA diameter (25% vs. 8%). The mean preoperative maximum AAA diameter was similar among the patients with the new (5.4 cm) or old (5.3 cm) Excluder.

WASHINGTON — The low-permeability version of the Gore Excluder stent graft appears to reduce the volume and diameter of abdominal aortic aneurysms at 1 year significantly more than did the older, more permeable version of the stent, according to the results of a prospective study comparing the two models.

The high rate of failure with the original Gore Excluder stent graft, in which the mean maximum abdominal aortic aneurysm (AAA) diameter increased by at least 5 mm in 36% of patients after 5 years, prompted the stent's manufacturer, W.L. Gore & Associates Inc., to add a new low-permeability layer between the device's expanded polytetrafluoroethylene layer and its reinforcing membrane, Dr. Manish Mehta said at the annual meeting of the Eastern Vascular Society.

The Food and Drug Administration approved the new device in July 2004.

In a series of 428 patients who received either the new or the old Excluder for AAA treatment during 2001–2005 at the Institute for Vascular Health and Disease at Albany (N.Y.) Medical College, Dr. Mehta and his colleagues compared the outcomes of 214 patients who had CT angiography imaging results available 1 year after the procedure.

The CT angiograms revealed that 114 consecutive patients with the low-permeability stent had significantly greater declines in mean AAA volume than 100 consecutive patients with the original type of stent (163 mL to 141 mL vs. 156 mL to 160 mL). The percentage of patients with more than a 5% drop in AAA volume also was significantly greater in patients with the new stent (52%) than in those with the old stent (6%), reported Dr. Mehta, a vascular surgeon at the institute.

Compared with recipients of the old stent graft, significantly fewer patients with the new device had more than a 5% increase in AAA volume (12% vs. 2.6%).

A significantly greater percentage of patients with the low-permeability stent had at least a 5-mm decrease in maximum AAA diameter (25% vs. 8%). The mean preoperative maximum AAA diameter was similar among the patients with the new (5.4 cm) or old (5.3 cm) Excluder.

WASHINGTON — The low-permeability version of the Gore Excluder stent graft appears to reduce the volume and diameter of abdominal aortic aneurysms at 1 year significantly more than did the older, more permeable version of the stent, according to the results of a prospective study comparing the two models.

The high rate of failure with the original Gore Excluder stent graft, in which the mean maximum abdominal aortic aneurysm (AAA) diameter increased by at least 5 mm in 36% of patients after 5 years, prompted the stent's manufacturer, W.L. Gore & Associates Inc., to add a new low-permeability layer between the device's expanded polytetrafluoroethylene layer and its reinforcing membrane, Dr. Manish Mehta said at the annual meeting of the Eastern Vascular Society.

The Food and Drug Administration approved the new device in July 2004.

In a series of 428 patients who received either the new or the old Excluder for AAA treatment during 2001–2005 at the Institute for Vascular Health and Disease at Albany (N.Y.) Medical College, Dr. Mehta and his colleagues compared the outcomes of 214 patients who had CT angiography imaging results available 1 year after the procedure.

The CT angiograms revealed that 114 consecutive patients with the low-permeability stent had significantly greater declines in mean AAA volume than 100 consecutive patients with the original type of stent (163 mL to 141 mL vs. 156 mL to 160 mL). The percentage of patients with more than a 5% drop in AAA volume also was significantly greater in patients with the new stent (52%) than in those with the old stent (6%), reported Dr. Mehta, a vascular surgeon at the institute.

Compared with recipients of the old stent graft, significantly fewer patients with the new device had more than a 5% increase in AAA volume (12% vs. 2.6%).

A significantly greater percentage of patients with the low-permeability stent had at least a 5-mm decrease in maximum AAA diameter (25% vs. 8%). The mean preoperative maximum AAA diameter was similar among the patients with the new (5.4 cm) or old (5.3 cm) Excluder.

CHICAGO — An investigational gabapentin prodrug may be an effective therapy for symptoms and sleep problems associated with restless legs syndrome, Dr. Arthur S. Walters reported at the annual meeting of the American Neurological Association.

The active compound gabapentin has already been shown to improve the sensory and motor symptoms of restless legs syndrome (RLS) and decrease periodic leg movements during sleep, but the drug is approved only for treating epilepsy and postherpetic neuralgia, according to Dr. Walters of the Seton Hall University School of Graduate Medical Education, Edison, N.J.

The gabapentin prodrug XP13512 has several potential advantages over standard gabapentin for treating RLS: The agent has linear pharmacokinetics, doesn't reach a saturation point, and is formulated for sustained release. The capacity for once-daily dosing differentiates gabapentin prodrug XP13512 from the active compound gabapentin (Neurontin), which cannot be manufactured in a sustained-release delivery and must be taken three to four times per day, Dr. Walters discussed on his poster at the meeting.

XenoPort Inc., the drug's manufacturer, has sponsored two phase II, randomized, double-blind trials. One of these trials was a crossover study with 38 patients testing 1,800 mg XP13512 against placebo. The other trial compared XP13512 at 600 mg and 1,200 mg and placebo in 95 patients without any crossover. In both studies, patients had RLS symptoms on at least 4 nights during a 7-day baseline period and had a score of at least 15 (out of a possible 40) on the International RLS Study Group rating scale (IRLS). Most patients were white and had a mean age of about 50 years.

Compared with patients given placebo, patients who were treated with the gabapentin prodrug had significantly greater improvement (decreases) in IRLS scores at doses of 1,800 mg (20.4 to 8.4 vs. 20.4 to 18.5) and 1,200 mg (22.4 to 6.3 vs. 22.4 to 13.5) at the end of the 2-week trial. The patients who received XP13512 at 1,200 mg also had significantly greater improvement than those who received 600 mg. Clinical global impressions of change from both patients and investigators followed the same trend and were significantly in favor of patients who received XP13512, reported Dr. Walters, who received compensation for consulting with XenoPort.

Polysomnographic assessments in the crossover study found that patients had significantly more total sleep time (25 minutes) while receiving the gabapentin prodrug than when they received placebo. In both studies, patients who received XP13512 had significantly fewer awakenings during the night and spent less time awake per night because of RLS symptoms.

CHICAGO — An investigational gabapentin prodrug may be an effective therapy for symptoms and sleep problems associated with restless legs syndrome, Dr. Arthur S. Walters reported at the annual meeting of the American Neurological Association.

The active compound gabapentin has already been shown to improve the sensory and motor symptoms of restless legs syndrome (RLS) and decrease periodic leg movements during sleep, but the drug is approved only for treating epilepsy and postherpetic neuralgia, according to Dr. Walters of the Seton Hall University School of Graduate Medical Education, Edison, N.J.

The gabapentin prodrug XP13512 has several potential advantages over standard gabapentin for treating RLS: The agent has linear pharmacokinetics, doesn't reach a saturation point, and is formulated for sustained release. The capacity for once-daily dosing differentiates gabapentin prodrug XP13512 from the active compound gabapentin (Neurontin), which cannot be manufactured in a sustained-release delivery and must be taken three to four times per day, Dr. Walters discussed on his poster at the meeting.

XenoPort Inc., the drug's manufacturer, has sponsored two phase II, randomized, double-blind trials. One of these trials was a crossover study with 38 patients testing 1,800 mg XP13512 against placebo. The other trial compared XP13512 at 600 mg and 1,200 mg and placebo in 95 patients without any crossover. In both studies, patients had RLS symptoms on at least 4 nights during a 7-day baseline period and had a score of at least 15 (out of a possible 40) on the International RLS Study Group rating scale (IRLS). Most patients were white and had a mean age of about 50 years.

Compared with patients given placebo, patients who were treated with the gabapentin prodrug had significantly greater improvement (decreases) in IRLS scores at doses of 1,800 mg (20.4 to 8.4 vs. 20.4 to 18.5) and 1,200 mg (22.4 to 6.3 vs. 22.4 to 13.5) at the end of the 2-week trial. The patients who received XP13512 at 1,200 mg also had significantly greater improvement than those who received 600 mg. Clinical global impressions of change from both patients and investigators followed the same trend and were significantly in favor of patients who received XP13512, reported Dr. Walters, who received compensation for consulting with XenoPort.

Polysomnographic assessments in the crossover study found that patients had significantly more total sleep time (25 minutes) while receiving the gabapentin prodrug than when they received placebo. In both studies, patients who received XP13512 had significantly fewer awakenings during the night and spent less time awake per night because of RLS symptoms.

CHICAGO — An investigational gabapentin prodrug may be an effective therapy for symptoms and sleep problems associated with restless legs syndrome, Dr. Arthur S. Walters reported at the annual meeting of the American Neurological Association.

The active compound gabapentin has already been shown to improve the sensory and motor symptoms of restless legs syndrome (RLS) and decrease periodic leg movements during sleep, but the drug is approved only for treating epilepsy and postherpetic neuralgia, according to Dr. Walters of the Seton Hall University School of Graduate Medical Education, Edison, N.J.

The gabapentin prodrug XP13512 has several potential advantages over standard gabapentin for treating RLS: The agent has linear pharmacokinetics, doesn't reach a saturation point, and is formulated for sustained release. The capacity for once-daily dosing differentiates gabapentin prodrug XP13512 from the active compound gabapentin (Neurontin), which cannot be manufactured in a sustained-release delivery and must be taken three to four times per day, Dr. Walters discussed on his poster at the meeting.

XenoPort Inc., the drug's manufacturer, has sponsored two phase II, randomized, double-blind trials. One of these trials was a crossover study with 38 patients testing 1,800 mg XP13512 against placebo. The other trial compared XP13512 at 600 mg and 1,200 mg and placebo in 95 patients without any crossover. In both studies, patients had RLS symptoms on at least 4 nights during a 7-day baseline period and had a score of at least 15 (out of a possible 40) on the International RLS Study Group rating scale (IRLS). Most patients were white and had a mean age of about 50 years.

Compared with patients given placebo, patients who were treated with the gabapentin prodrug had significantly greater improvement (decreases) in IRLS scores at doses of 1,800 mg (20.4 to 8.4 vs. 20.4 to 18.5) and 1,200 mg (22.4 to 6.3 vs. 22.4 to 13.5) at the end of the 2-week trial. The patients who received XP13512 at 1,200 mg also had significantly greater improvement than those who received 600 mg. Clinical global impressions of change from both patients and investigators followed the same trend and were significantly in favor of patients who received XP13512, reported Dr. Walters, who received compensation for consulting with XenoPort.

Polysomnographic assessments in the crossover study found that patients had significantly more total sleep time (25 minutes) while receiving the gabapentin prodrug than when they received placebo. In both studies, patients who received XP13512 had significantly fewer awakenings during the night and spent less time awake per night because of RLS symptoms.

BETHESDA, MD. – A complex set of predisposing, precipitating, and perpetuating factors appears to play a major role in driving the behavioral and neurochemical changes of patients with anorexia or bulimia, Craig Johnson, Ph.D., said at the annual conference of the National Eating Disorders Association.

“A belief system develops, and from that belief system, behaviors emerge. When those behaviors emerge, that also starts to alter the psychology and physiology of the patient and can set up these perpetuating factors so that they feed back on the predisposing and precipitating factors,” said Dr. Johnson, founder and director of the eating disorders program at the Laureate Psychiatric Clinic and Hospital in Tulsa, Okla.

The factors that serve to perpetuate an eating disorder may have little to do with why the illness is continuing. The structural and functional changes to neurochemical pathways in the brain that occurred as a result of the eating disorder behavior will continue to reinforce whatever stimulation was gained from the behavior, he said.

“Without exception, patients we're taking care of entered into these behaviors to try to fix something in themselves. It was a self-improvement strategy. They thought they were doing a good thing. They were doing the same things they saw encouraged throughout our culture,” Dr. Johnson said.

As they lost weight or altered their neurochemistry, though, “they stepped on a land mine, which is going to have a strong genetic predisposition to turn something on in their brain, which then sends them cascading down that road of being obsessed with weight loss and being compelled to accomplish it,” he explained.

“Eating disorders are as heritable, have the same level of relative risk, and look to be as genetically mediated as the other major psychiatric illnesses,” Dr. Johnson said.

If a relative has anorexia nervosa, other members of the family are 12 times more likely to develop the disorder than members of the general population. Similarly, if one family member has bulimia nervosa, other members are four times more likely to have it.

About two-thirds of eating disorder patients have a comorbid diagnosis of anxiety or depression, which predates the onset of the eating disorder in about half of such patients, he said.

Some patients also have an impaired ability to work with different sets of challenges on neuropsychological tests, although this measure is not correlated with intelligence. These test results “make sense, in terms of what we see happening to them when they move into increasing levels of complexity developmentally, starting with puberty,” he said.

Even though he and his colleagues are seeing gender, ethnic, and socioeconomic drift in the epidemiology of anorexia nervosa and bulimia, Dr. Johnson noted that they are still illnesses that primarily affect white females. Girls who drop below about 17% body fat lose the secondary sexual characteristics associated with puberty and flatten out their hormone profiles so that they don't “feel” the effects of puberty, Dr. Johnson said.

“In our treatment center, one of the things we want to know as soon as we can is where the menstrual threshold is. At what point with our weight restoration are we going to be sending them clearly on the other side of puberty?” he said.

If patients do not stay in treatment long enough to restore their weight past the menstrual threshold, they will not have dealt adequately with their phobic fear of menstruation, he said.

Patients with bulimia nervosa often report that bingeing on carbohydrate-rich food calms them down, which may be the result of increased blood levels of tryptophan, an amino acid that can pass the blood-brain barrier and is synthesized into serotonin; treatment with selective serotonin reuptake inhibitors may make this effect even more pronounced by increasing the amount of serotonin available at synapses, Dr. Johnson suggested.

Vomiting also causes a sedating effect in bulimic patients because of the release of vasopressin. An autoaddiction to the vasopressin release may explain why binges become smaller and vomiting becomes disproportionate to the volume of food, he said.

Excessive exercise also appears to be a reinforcing and possibly anorexia-inducing behavior. “Running seems to have some unique interaction with restricting behavior that essentially stimulates something very, very toxic for the patients that have the more severe forms of the illness. We've found that very few patients are able to successfully return to running in our treatment program,” he said.

Functional MRI studies of the brains of anorexic patients and healthy controls have revealed some striking differences in dopamine pathways that suggest that patients with the disorder do not discriminate between positive and negative feedback and have a blunted response to pleasurable stimuli, according to Dr. Walter Kaye, who gave a separate presentation during the same session at the conference.

During a gambling task in which participants could win or lose money, trials in which patients with anorexia nervosa won money produced brain activity similar to that of control patients during winning trials, but anorexic patients who lost money also had brain activity similar to that of controls who won money, said Dr. Kaye, research director of the eating disorder program at the University of Pittsburgh.

In a separate fMRI study, the taste of sugar produced blunted responses in the insula (the primary taste cortex) of recovered anorexic patients, compared with healthy controls. Unlike in the healthy patients, however, there was no correlation between the taster's rating of pleasantness and the insula's response to sugar in recovered anorexic individuals, he noted.

Even before these data can be used to develop new treatments, it will be useful to let patients understand that this particular temperament is wired into their brains and that they might be able to learn to modulate their feelings and thoughts and develop adaptive coping strategies, said Dr. Kaye, also of the University of California, San Diego.

BETHESDA, MD. – A complex set of predisposing, precipitating, and perpetuating factors appears to play a major role in driving the behavioral and neurochemical changes of patients with anorexia or bulimia, Craig Johnson, Ph.D., said at the annual conference of the National Eating Disorders Association.

“A belief system develops, and from that belief system, behaviors emerge. When those behaviors emerge, that also starts to alter the psychology and physiology of the patient and can set up these perpetuating factors so that they feed back on the predisposing and precipitating factors,” said Dr. Johnson, founder and director of the eating disorders program at the Laureate Psychiatric Clinic and Hospital in Tulsa, Okla.

The factors that serve to perpetuate an eating disorder may have little to do with why the illness is continuing. The structural and functional changes to neurochemical pathways in the brain that occurred as a result of the eating disorder behavior will continue to reinforce whatever stimulation was gained from the behavior, he said.

“Without exception, patients we're taking care of entered into these behaviors to try to fix something in themselves. It was a self-improvement strategy. They thought they were doing a good thing. They were doing the same things they saw encouraged throughout our culture,” Dr. Johnson said.

As they lost weight or altered their neurochemistry, though, “they stepped on a land mine, which is going to have a strong genetic predisposition to turn something on in their brain, which then sends them cascading down that road of being obsessed with weight loss and being compelled to accomplish it,” he explained.

“Eating disorders are as heritable, have the same level of relative risk, and look to be as genetically mediated as the other major psychiatric illnesses,” Dr. Johnson said.

If a relative has anorexia nervosa, other members of the family are 12 times more likely to develop the disorder than members of the general population. Similarly, if one family member has bulimia nervosa, other members are four times more likely to have it.

About two-thirds of eating disorder patients have a comorbid diagnosis of anxiety or depression, which predates the onset of the eating disorder in about half of such patients, he said.

Some patients also have an impaired ability to work with different sets of challenges on neuropsychological tests, although this measure is not correlated with intelligence. These test results “make sense, in terms of what we see happening to them when they move into increasing levels of complexity developmentally, starting with puberty,” he said.

Even though he and his colleagues are seeing gender, ethnic, and socioeconomic drift in the epidemiology of anorexia nervosa and bulimia, Dr. Johnson noted that they are still illnesses that primarily affect white females. Girls who drop below about 17% body fat lose the secondary sexual characteristics associated with puberty and flatten out their hormone profiles so that they don't “feel” the effects of puberty, Dr. Johnson said.

“In our treatment center, one of the things we want to know as soon as we can is where the menstrual threshold is. At what point with our weight restoration are we going to be sending them clearly on the other side of puberty?” he said.

If patients do not stay in treatment long enough to restore their weight past the menstrual threshold, they will not have dealt adequately with their phobic fear of menstruation, he said.

Patients with bulimia nervosa often report that bingeing on carbohydrate-rich food calms them down, which may be the result of increased blood levels of tryptophan, an amino acid that can pass the blood-brain barrier and is synthesized into serotonin; treatment with selective serotonin reuptake inhibitors may make this effect even more pronounced by increasing the amount of serotonin available at synapses, Dr. Johnson suggested.

Vomiting also causes a sedating effect in bulimic patients because of the release of vasopressin. An autoaddiction to the vasopressin release may explain why binges become smaller and vomiting becomes disproportionate to the volume of food, he said.

Excessive exercise also appears to be a reinforcing and possibly anorexia-inducing behavior. “Running seems to have some unique interaction with restricting behavior that essentially stimulates something very, very toxic for the patients that have the more severe forms of the illness. We've found that very few patients are able to successfully return to running in our treatment program,” he said.

Functional MRI studies of the brains of anorexic patients and healthy controls have revealed some striking differences in dopamine pathways that suggest that patients with the disorder do not discriminate between positive and negative feedback and have a blunted response to pleasurable stimuli, according to Dr. Walter Kaye, who gave a separate presentation during the same session at the conference.

During a gambling task in which participants could win or lose money, trials in which patients with anorexia nervosa won money produced brain activity similar to that of control patients during winning trials, but anorexic patients who lost money also had brain activity similar to that of controls who won money, said Dr. Kaye, research director of the eating disorder program at the University of Pittsburgh.

In a separate fMRI study, the taste of sugar produced blunted responses in the insula (the primary taste cortex) of recovered anorexic patients, compared with healthy controls. Unlike in the healthy patients, however, there was no correlation between the taster's rating of pleasantness and the insula's response to sugar in recovered anorexic individuals, he noted.

Even before these data can be used to develop new treatments, it will be useful to let patients understand that this particular temperament is wired into their brains and that they might be able to learn to modulate their feelings and thoughts and develop adaptive coping strategies, said Dr. Kaye, also of the University of California, San Diego.

BETHESDA, MD. – A complex set of predisposing, precipitating, and perpetuating factors appears to play a major role in driving the behavioral and neurochemical changes of patients with anorexia or bulimia, Craig Johnson, Ph.D., said at the annual conference of the National Eating Disorders Association.

“A belief system develops, and from that belief system, behaviors emerge. When those behaviors emerge, that also starts to alter the psychology and physiology of the patient and can set up these perpetuating factors so that they feed back on the predisposing and precipitating factors,” said Dr. Johnson, founder and director of the eating disorders program at the Laureate Psychiatric Clinic and Hospital in Tulsa, Okla.

The factors that serve to perpetuate an eating disorder may have little to do with why the illness is continuing. The structural and functional changes to neurochemical pathways in the brain that occurred as a result of the eating disorder behavior will continue to reinforce whatever stimulation was gained from the behavior, he said.

“Without exception, patients we're taking care of entered into these behaviors to try to fix something in themselves. It was a self-improvement strategy. They thought they were doing a good thing. They were doing the same things they saw encouraged throughout our culture,” Dr. Johnson said.

As they lost weight or altered their neurochemistry, though, “they stepped on a land mine, which is going to have a strong genetic predisposition to turn something on in their brain, which then sends them cascading down that road of being obsessed with weight loss and being compelled to accomplish it,” he explained.

“Eating disorders are as heritable, have the same level of relative risk, and look to be as genetically mediated as the other major psychiatric illnesses,” Dr. Johnson said.

If a relative has anorexia nervosa, other members of the family are 12 times more likely to develop the disorder than members of the general population. Similarly, if one family member has bulimia nervosa, other members are four times more likely to have it.

About two-thirds of eating disorder patients have a comorbid diagnosis of anxiety or depression, which predates the onset of the eating disorder in about half of such patients, he said.

Some patients also have an impaired ability to work with different sets of challenges on neuropsychological tests, although this measure is not correlated with intelligence. These test results “make sense, in terms of what we see happening to them when they move into increasing levels of complexity developmentally, starting with puberty,” he said.

Even though he and his colleagues are seeing gender, ethnic, and socioeconomic drift in the epidemiology of anorexia nervosa and bulimia, Dr. Johnson noted that they are still illnesses that primarily affect white females. Girls who drop below about 17% body fat lose the secondary sexual characteristics associated with puberty and flatten out their hormone profiles so that they don't “feel” the effects of puberty, Dr. Johnson said.

“In our treatment center, one of the things we want to know as soon as we can is where the menstrual threshold is. At what point with our weight restoration are we going to be sending them clearly on the other side of puberty?” he said.

If patients do not stay in treatment long enough to restore their weight past the menstrual threshold, they will not have dealt adequately with their phobic fear of menstruation, he said.

Patients with bulimia nervosa often report that bingeing on carbohydrate-rich food calms them down, which may be the result of increased blood levels of tryptophan, an amino acid that can pass the blood-brain barrier and is synthesized into serotonin; treatment with selective serotonin reuptake inhibitors may make this effect even more pronounced by increasing the amount of serotonin available at synapses, Dr. Johnson suggested.

Vomiting also causes a sedating effect in bulimic patients because of the release of vasopressin. An autoaddiction to the vasopressin release may explain why binges become smaller and vomiting becomes disproportionate to the volume of food, he said.

Excessive exercise also appears to be a reinforcing and possibly anorexia-inducing behavior. “Running seems to have some unique interaction with restricting behavior that essentially stimulates something very, very toxic for the patients that have the more severe forms of the illness. We've found that very few patients are able to successfully return to running in our treatment program,” he said.

Functional MRI studies of the brains of anorexic patients and healthy controls have revealed some striking differences in dopamine pathways that suggest that patients with the disorder do not discriminate between positive and negative feedback and have a blunted response to pleasurable stimuli, according to Dr. Walter Kaye, who gave a separate presentation during the same session at the conference.

During a gambling task in which participants could win or lose money, trials in which patients with anorexia nervosa won money produced brain activity similar to that of control patients during winning trials, but anorexic patients who lost money also had brain activity similar to that of controls who won money, said Dr. Kaye, research director of the eating disorder program at the University of Pittsburgh.

In a separate fMRI study, the taste of sugar produced blunted responses in the insula (the primary taste cortex) of recovered anorexic patients, compared with healthy controls. Unlike in the healthy patients, however, there was no correlation between the taster's rating of pleasantness and the insula's response to sugar in recovered anorexic individuals, he noted.

Even before these data can be used to develop new treatments, it will be useful to let patients understand that this particular temperament is wired into their brains and that they might be able to learn to modulate their feelings and thoughts and develop adaptive coping strategies, said Dr. Kaye, also of the University of California, San Diego.

CHICAGO – A high level of tumor necrosis factor-α in cerebrospinal fluid, but not serum, may be an early indicator for neuroinflammation and possibly autism, according to a study of eight autistic children with regression.

Although recent reports have found elevated levels of proinflammatory cytokines in brain tissue and cerebrospinal fluid (CSF) of autistic patients, no studies to date have specifically examined the level of tumor necrosis factor-α (TNF-α) in patients with autistic regression, Dr. Michael G. Chez reported during a poster session at the annual meeting of the American Neurological Association.

The mean concentration of TNF-α in the CSF of eight male patients who had autistic regression at an age of 15–24 months was significantly higher than it was in sera collected at the same time from the patients at ages ranging from 2.1 years to 9.5 years (62.6 pg/mL vs. 3.5 pg/mL), according to Dr. Chez of the department of neurology at Chicago Medical School, North Chicago.

The CSF-to-serum ratio of TNF-α in autistic patients (24.4:1.0) was higher than what has been reported for other inflammation-related disorders, such as meningitis, multiple sclerosis, systemic lupus erythematosus, HIV, traumatic brain injury, dementia, and stroke, all of which had ratios near 1.0:1.0.

The CSF-to-serum ratio of TNF-α in four of the patients who were previously treated with prednisone, thalidomide, or turmeric for “presumed autoimmune issues” was significantly lower than the other four patients who had no prior treatments (6.1:1.0 vs. 33.2:1.0).

CHICAGO – A high level of tumor necrosis factor-α in cerebrospinal fluid, but not serum, may be an early indicator for neuroinflammation and possibly autism, according to a study of eight autistic children with regression.

Although recent reports have found elevated levels of proinflammatory cytokines in brain tissue and cerebrospinal fluid (CSF) of autistic patients, no studies to date have specifically examined the level of tumor necrosis factor-α (TNF-α) in patients with autistic regression, Dr. Michael G. Chez reported during a poster session at the annual meeting of the American Neurological Association.

The mean concentration of TNF-α in the CSF of eight male patients who had autistic regression at an age of 15–24 months was significantly higher than it was in sera collected at the same time from the patients at ages ranging from 2.1 years to 9.5 years (62.6 pg/mL vs. 3.5 pg/mL), according to Dr. Chez of the department of neurology at Chicago Medical School, North Chicago.

The CSF-to-serum ratio of TNF-α in autistic patients (24.4:1.0) was higher than what has been reported for other inflammation-related disorders, such as meningitis, multiple sclerosis, systemic lupus erythematosus, HIV, traumatic brain injury, dementia, and stroke, all of which had ratios near 1.0:1.0.

The CSF-to-serum ratio of TNF-α in four of the patients who were previously treated with prednisone, thalidomide, or turmeric for “presumed autoimmune issues” was significantly lower than the other four patients who had no prior treatments (6.1:1.0 vs. 33.2:1.0).

CHICAGO – A high level of tumor necrosis factor-α in cerebrospinal fluid, but not serum, may be an early indicator for neuroinflammation and possibly autism, according to a study of eight autistic children with regression.

Although recent reports have found elevated levels of proinflammatory cytokines in brain tissue and cerebrospinal fluid (CSF) of autistic patients, no studies to date have specifically examined the level of tumor necrosis factor-α (TNF-α) in patients with autistic regression, Dr. Michael G. Chez reported during a poster session at the annual meeting of the American Neurological Association.

The mean concentration of TNF-α in the CSF of eight male patients who had autistic regression at an age of 15–24 months was significantly higher than it was in sera collected at the same time from the patients at ages ranging from 2.1 years to 9.5 years (62.6 pg/mL vs. 3.5 pg/mL), according to Dr. Chez of the department of neurology at Chicago Medical School, North Chicago.

The CSF-to-serum ratio of TNF-α in autistic patients (24.4:1.0) was higher than what has been reported for other inflammation-related disorders, such as meningitis, multiple sclerosis, systemic lupus erythematosus, HIV, traumatic brain injury, dementia, and stroke, all of which had ratios near 1.0:1.0.

The CSF-to-serum ratio of TNF-α in four of the patients who were previously treated with prednisone, thalidomide, or turmeric for “presumed autoimmune issues” was significantly lower than the other four patients who had no prior treatments (6.1:1.0 vs. 33.2:1.0).

CHICAGO – The β-blocker propranolol may help some aphasic patients communicate more easily, at least in the short term, Dr. Yutaka Tanaka reported in a poster session at the annual meeting of the American Neurological Association.

β-blockers have been shown to lessen performance anxiety in nervous musicians and students.

This gave Dr. Tanaka and his colleagues the idea that the drugs might have the same effect for aphasic patients with performance anxiety.

Aphasic patients have been reported to score better on tests of functional communication than on more formal tests of specific linguistic ability, he said.

The investigators tested patients and controls on naming (Boston Naming Test) and verbal fluency (FAS; listing animals, vegetables, or numbers for 1 minute) for the first time 90 minutes after 10-mg propranolol was administered and at a second visit without any medication, said Dr. Tanaka, who is a neurologist in private practice in Ikoma-Gun, Japan.

Of 6 patients with Broca's aphasia and 4 with Wernicke's aphasia (mean age of 70 years), all 10 showed significant improvement on all of the tests after receiving propranolol. In all of the patients, the testing occurred more than 6 months after the onset of aphasia.

Propranolol did not significantly alter the performance of nine young or nine elderly control subjects on any of the tests.

Nine middle-aged control individuals significantly improved on two tests of fluency but not on the naming test when pretreated with propranolol, he said.

“We postulate that the patients with aphasia were more anxious than the other groups with regard to language tasks, and thus benefited from treatment with the β-blockers,” Dr. Tanaka said.

CHICAGO – The β-blocker propranolol may help some aphasic patients communicate more easily, at least in the short term, Dr. Yutaka Tanaka reported in a poster session at the annual meeting of the American Neurological Association.

β-blockers have been shown to lessen performance anxiety in nervous musicians and students.

This gave Dr. Tanaka and his colleagues the idea that the drugs might have the same effect for aphasic patients with performance anxiety.

Aphasic patients have been reported to score better on tests of functional communication than on more formal tests of specific linguistic ability, he said.

The investigators tested patients and controls on naming (Boston Naming Test) and verbal fluency (FAS; listing animals, vegetables, or numbers for 1 minute) for the first time 90 minutes after 10-mg propranolol was administered and at a second visit without any medication, said Dr. Tanaka, who is a neurologist in private practice in Ikoma-Gun, Japan.

Of 6 patients with Broca's aphasia and 4 with Wernicke's aphasia (mean age of 70 years), all 10 showed significant improvement on all of the tests after receiving propranolol. In all of the patients, the testing occurred more than 6 months after the onset of aphasia.

Propranolol did not significantly alter the performance of nine young or nine elderly control subjects on any of the tests.

Nine middle-aged control individuals significantly improved on two tests of fluency but not on the naming test when pretreated with propranolol, he said.

“We postulate that the patients with aphasia were more anxious than the other groups with regard to language tasks, and thus benefited from treatment with the β-blockers,” Dr. Tanaka said.

CHICAGO – The β-blocker propranolol may help some aphasic patients communicate more easily, at least in the short term, Dr. Yutaka Tanaka reported in a poster session at the annual meeting of the American Neurological Association.

β-blockers have been shown to lessen performance anxiety in nervous musicians and students.

This gave Dr. Tanaka and his colleagues the idea that the drugs might have the same effect for aphasic patients with performance anxiety.

Aphasic patients have been reported to score better on tests of functional communication than on more formal tests of specific linguistic ability, he said.

The investigators tested patients and controls on naming (Boston Naming Test) and verbal fluency (FAS; listing animals, vegetables, or numbers for 1 minute) for the first time 90 minutes after 10-mg propranolol was administered and at a second visit without any medication, said Dr. Tanaka, who is a neurologist in private practice in Ikoma-Gun, Japan.

Of 6 patients with Broca's aphasia and 4 with Wernicke's aphasia (mean age of 70 years), all 10 showed significant improvement on all of the tests after receiving propranolol. In all of the patients, the testing occurred more than 6 months after the onset of aphasia.

Propranolol did not significantly alter the performance of nine young or nine elderly control subjects on any of the tests.

Nine middle-aged control individuals significantly improved on two tests of fluency but not on the naming test when pretreated with propranolol, he said.

“We postulate that the patients with aphasia were more anxious than the other groups with regard to language tasks, and thus benefited from treatment with the β-blockers,” Dr. Tanaka said.