Michele G. Sullivan

HENDERSON, NEV. – The concomitant and comorbid conditions associated with migraine and chronic daily headache offer both therapeutic challenges and opportunities, Dr. Elizabeth W. Loder said at a symposium sponsored by the American Headache Society.

These problems may not be severe enough to warrant inpatient therapy on their own, but when combined with headache, they result in such a burden of symptoms that hospitalization might make sense, said Dr. Loder, director of the headache management program at Spaulding Rehabilitation Hospital in Boston.

“Sometimes it's expeditious to do other things in the hospital, even though you're not necessarily admitting them for that reason,” she said. “For example, I think it's very useful to have polysomnography for oxygen levels done on all your headache patients admitted to the hospital. You'll find a lot of sleep apnea that way. Treating that in itself is important, but it may improve the headache situation as well.”

Some of the most frequent findings are other pain disorders. “It's very uncommon to have a headache patient in the hospital who doesn't also have some other pain disorder,” Dr. Loder said.

Among the most common pain disorders in this population are fibromyalgia, back and neck pain, musculoskeletal pain, irritable bowel syndrome, and noncardiac chest pain. Physicians should be wary of prescribing opioids or narcotics to headache patients who have these symptoms, because “there is a risk that the patient will start to use them for the other pain problems, and then will have difficulty controlling the use. There's also new evidence that long-term use of opioids actually may aggravate pain and make the patient less responsive to other treatment,” she said.

Raynaud's disease is also more common in migraine patients, as is a combination of Raynaud's and noncardiac chest pain. The cluster of symptoms may stem from underlying microvascular disease.

“The presence of Raynaud's has some treatment implications for migraineurs,” Dr. Loder said. Avoid the use of β-blockers and ergots, as they exacerbate Raynaud's. Calcium channel blockers, however, may improve the Raynaud's symptoms while acting as a migraine preventive.

Microvascular disease may also be implicated in the connection of migraine with coronary heart disease, Dr. Loder said. Numerous studies have documented the association, including the National Health and Nutrition Examination Survey, which found a doubling of the risk of heart attack in migraineurs. Subsequent studies have not upheld that conclusion.

“The evidence is conflicting,” Dr. Loder said. “None of the studies were designed specifically to look at the association of migraine with heart disease, so you're relying on previously diagnosed migraine” as the variable. Since most diagnosed migraine usually is severe, often with aura, the study populations are probably skewed. “What we are probably seeing is the incidence of cardiovascular disease in this particular population. But the definite statement on this awaits a prospective study.”

She said, however, that primary heart disease, including uncontrolled hypertension, severely limits migraine treatment options because triptans and dihydroergotamine are contraindicated in these patients. “Controlled hypertension is not a contraindication for triptan use, but patients might have other risk factors, so you might feel more comfortable assessing them in the hospital,” Dr. Loder said.

HENDERSON, NEV. – The concomitant and comorbid conditions associated with migraine and chronic daily headache offer both therapeutic challenges and opportunities, Dr. Elizabeth W. Loder said at a symposium sponsored by the American Headache Society.

These problems may not be severe enough to warrant inpatient therapy on their own, but when combined with headache, they result in such a burden of symptoms that hospitalization might make sense, said Dr. Loder, director of the headache management program at Spaulding Rehabilitation Hospital in Boston.

“Sometimes it's expeditious to do other things in the hospital, even though you're not necessarily admitting them for that reason,” she said. “For example, I think it's very useful to have polysomnography for oxygen levels done on all your headache patients admitted to the hospital. You'll find a lot of sleep apnea that way. Treating that in itself is important, but it may improve the headache situation as well.”

Some of the most frequent findings are other pain disorders. “It's very uncommon to have a headache patient in the hospital who doesn't also have some other pain disorder,” Dr. Loder said.

Among the most common pain disorders in this population are fibromyalgia, back and neck pain, musculoskeletal pain, irritable bowel syndrome, and noncardiac chest pain. Physicians should be wary of prescribing opioids or narcotics to headache patients who have these symptoms, because “there is a risk that the patient will start to use them for the other pain problems, and then will have difficulty controlling the use. There's also new evidence that long-term use of opioids actually may aggravate pain and make the patient less responsive to other treatment,” she said.

Raynaud's disease is also more common in migraine patients, as is a combination of Raynaud's and noncardiac chest pain. The cluster of symptoms may stem from underlying microvascular disease.

“The presence of Raynaud's has some treatment implications for migraineurs,” Dr. Loder said. Avoid the use of β-blockers and ergots, as they exacerbate Raynaud's. Calcium channel blockers, however, may improve the Raynaud's symptoms while acting as a migraine preventive.

Microvascular disease may also be implicated in the connection of migraine with coronary heart disease, Dr. Loder said. Numerous studies have documented the association, including the National Health and Nutrition Examination Survey, which found a doubling of the risk of heart attack in migraineurs. Subsequent studies have not upheld that conclusion.

“The evidence is conflicting,” Dr. Loder said. “None of the studies were designed specifically to look at the association of migraine with heart disease, so you're relying on previously diagnosed migraine” as the variable. Since most diagnosed migraine usually is severe, often with aura, the study populations are probably skewed. “What we are probably seeing is the incidence of cardiovascular disease in this particular population. But the definite statement on this awaits a prospective study.”

She said, however, that primary heart disease, including uncontrolled hypertension, severely limits migraine treatment options because triptans and dihydroergotamine are contraindicated in these patients. “Controlled hypertension is not a contraindication for triptan use, but patients might have other risk factors, so you might feel more comfortable assessing them in the hospital,” Dr. Loder said.

HENDERSON, NEV. – The concomitant and comorbid conditions associated with migraine and chronic daily headache offer both therapeutic challenges and opportunities, Dr. Elizabeth W. Loder said at a symposium sponsored by the American Headache Society.

These problems may not be severe enough to warrant inpatient therapy on their own, but when combined with headache, they result in such a burden of symptoms that hospitalization might make sense, said Dr. Loder, director of the headache management program at Spaulding Rehabilitation Hospital in Boston.

“Sometimes it's expeditious to do other things in the hospital, even though you're not necessarily admitting them for that reason,” she said. “For example, I think it's very useful to have polysomnography for oxygen levels done on all your headache patients admitted to the hospital. You'll find a lot of sleep apnea that way. Treating that in itself is important, but it may improve the headache situation as well.”

Some of the most frequent findings are other pain disorders. “It's very uncommon to have a headache patient in the hospital who doesn't also have some other pain disorder,” Dr. Loder said.

Among the most common pain disorders in this population are fibromyalgia, back and neck pain, musculoskeletal pain, irritable bowel syndrome, and noncardiac chest pain. Physicians should be wary of prescribing opioids or narcotics to headache patients who have these symptoms, because “there is a risk that the patient will start to use them for the other pain problems, and then will have difficulty controlling the use. There's also new evidence that long-term use of opioids actually may aggravate pain and make the patient less responsive to other treatment,” she said.

Raynaud's disease is also more common in migraine patients, as is a combination of Raynaud's and noncardiac chest pain. The cluster of symptoms may stem from underlying microvascular disease.

“The presence of Raynaud's has some treatment implications for migraineurs,” Dr. Loder said. Avoid the use of β-blockers and ergots, as they exacerbate Raynaud's. Calcium channel blockers, however, may improve the Raynaud's symptoms while acting as a migraine preventive.

Microvascular disease may also be implicated in the connection of migraine with coronary heart disease, Dr. Loder said. Numerous studies have documented the association, including the National Health and Nutrition Examination Survey, which found a doubling of the risk of heart attack in migraineurs. Subsequent studies have not upheld that conclusion.

“The evidence is conflicting,” Dr. Loder said. “None of the studies were designed specifically to look at the association of migraine with heart disease, so you're relying on previously diagnosed migraine” as the variable. Since most diagnosed migraine usually is severe, often with aura, the study populations are probably skewed. “What we are probably seeing is the incidence of cardiovascular disease in this particular population. But the definite statement on this awaits a prospective study.”

She said, however, that primary heart disease, including uncontrolled hypertension, severely limits migraine treatment options because triptans and dihydroergotamine are contraindicated in these patients. “Controlled hypertension is not a contraindication for triptan use, but patients might have other risk factors, so you might feel more comfortable assessing them in the hospital,” Dr. Loder said.

HENDERSON, NEV. – Treating medication overuse headache involves a three-pronged approach of patient education, teaching pain coping skills, and addressing psychological issues that put patients at risk for relapse, Alvin E. Lake III, Ph.D., said at a symposium sponsored by the American Headache Society.

Most patients don't understand that excessive use of opioids can actually make them hypersensitive to pain, said Dr. Lake of the Michigan Head Pain and Neurological Institute, Ann Arbor. “They believe the pain is stronger than the medication, not that the medication is actually making them worse.” This thought process can be the root of ever-increasing medication use, as the patient experiences “pain anxiety” and attempts to forestall pain by premedicating.

The first step is to teach patients how medication overuse exacerbates headache pain, he said. Only when they have a clear understanding of this relationship will they be open to adhering to medication limits.

Sustained opioid use downregulates opioid receptors and upregulates excitatory receptors. This results in increased synthesis of excitatory neuropeptides. “Opioid tolerance is a red flag for induced abnormal pain sensitivity,” Dr. Lake said.

Overusing analgesics also interferes with effective prophylaxis, he said, citing a “seminal” 1990 study in which all patients received the same training in coping skills. Those who discontinued their daily analgesic and got a new prophylactic drug experienced the biggest improvement with their headaches.

Those who discontinued their analgesic but stayed on the same preventative improved as well, although not as much, while those who continued their daily analgesic experienced almost no improvement (Headache 1990;30:634–8).

“This study, which I use as a teaching tool, also shows patients that improvement doesn't happen immediately. They need to stay the course. It takes time for the receptors to remodulate, and how much time depends on how long they've been taking the medication and how much they've been on,” Dr. Lake said.

Simply taking away the analgesic isn't the answer, he stressed. Patients need to understand that drugs are not the only way to alleviate headaches, and that they will probably have to tolerate some level of pain. “The evidence, clinically and empirically, shows that it's very difficult for these patients to move to pain-free days. They have to find ways of dealing with headache that doesn't involve drugs.”

Biofeedback, stress management, and antidepressants all may be effective tools in relearning responses to headache pain. A 2001 study concluded that a combination of stress management and antidepressants was more effective than was either treatment alone in reducing chronic tension-type headache (JAMA 2001;285:2208–15).

And a 2002 study of medication overuse relapse showed that 3 years after medication withdrawal, patients on a combination of biofeedback and prophylactic medication experienced significantly fewer headaches per month and used less analgesic medication per month than did those on prophylaxis only (Headache 2002;42:483–90).

Treating any comorbid psychiatric disorder is critical, Dr. Lake said. His own unpublished study of 267 consecutive patients shows how common psychiatric disorders are in headache patients: All of the patients had at least one Axis I disorder, including depression (70%) and anxiety (40%). Another 26% had an Axis II personality disorder. Of those with an Axis II disorder, 63% had medication overuse headache, compared with 42% of those without such a disorder. The presence of an Axis II disorder was significantly associated with a poor long-term outcome.

Hospitalization may be the best way to assess the presence of these additional problems. “This gives you an opportunity to observe not only the patient's behavior, but family interactions and marital problems that you might not see otherwise. When they come into your office they may be able to pull it all together for a half an hour, but when you see them day in and day out, you have the opportunity to get to know the patient and family. It's all right there in front of you,” Dr. Lake said.

HENDERSON, NEV. – Treating medication overuse headache involves a three-pronged approach of patient education, teaching pain coping skills, and addressing psychological issues that put patients at risk for relapse, Alvin E. Lake III, Ph.D., said at a symposium sponsored by the American Headache Society.

Most patients don't understand that excessive use of opioids can actually make them hypersensitive to pain, said Dr. Lake of the Michigan Head Pain and Neurological Institute, Ann Arbor. “They believe the pain is stronger than the medication, not that the medication is actually making them worse.” This thought process can be the root of ever-increasing medication use, as the patient experiences “pain anxiety” and attempts to forestall pain by premedicating.

The first step is to teach patients how medication overuse exacerbates headache pain, he said. Only when they have a clear understanding of this relationship will they be open to adhering to medication limits.

Sustained opioid use downregulates opioid receptors and upregulates excitatory receptors. This results in increased synthesis of excitatory neuropeptides. “Opioid tolerance is a red flag for induced abnormal pain sensitivity,” Dr. Lake said.

Overusing analgesics also interferes with effective prophylaxis, he said, citing a “seminal” 1990 study in which all patients received the same training in coping skills. Those who discontinued their daily analgesic and got a new prophylactic drug experienced the biggest improvement with their headaches.

Those who discontinued their analgesic but stayed on the same preventative improved as well, although not as much, while those who continued their daily analgesic experienced almost no improvement (Headache 1990;30:634–8).

“This study, which I use as a teaching tool, also shows patients that improvement doesn't happen immediately. They need to stay the course. It takes time for the receptors to remodulate, and how much time depends on how long they've been taking the medication and how much they've been on,” Dr. Lake said.

Simply taking away the analgesic isn't the answer, he stressed. Patients need to understand that drugs are not the only way to alleviate headaches, and that they will probably have to tolerate some level of pain. “The evidence, clinically and empirically, shows that it's very difficult for these patients to move to pain-free days. They have to find ways of dealing with headache that doesn't involve drugs.”

Biofeedback, stress management, and antidepressants all may be effective tools in relearning responses to headache pain. A 2001 study concluded that a combination of stress management and antidepressants was more effective than was either treatment alone in reducing chronic tension-type headache (JAMA 2001;285:2208–15).

And a 2002 study of medication overuse relapse showed that 3 years after medication withdrawal, patients on a combination of biofeedback and prophylactic medication experienced significantly fewer headaches per month and used less analgesic medication per month than did those on prophylaxis only (Headache 2002;42:483–90).

Treating any comorbid psychiatric disorder is critical, Dr. Lake said. His own unpublished study of 267 consecutive patients shows how common psychiatric disorders are in headache patients: All of the patients had at least one Axis I disorder, including depression (70%) and anxiety (40%). Another 26% had an Axis II personality disorder. Of those with an Axis II disorder, 63% had medication overuse headache, compared with 42% of those without such a disorder. The presence of an Axis II disorder was significantly associated with a poor long-term outcome.

Hospitalization may be the best way to assess the presence of these additional problems. “This gives you an opportunity to observe not only the patient's behavior, but family interactions and marital problems that you might not see otherwise. When they come into your office they may be able to pull it all together for a half an hour, but when you see them day in and day out, you have the opportunity to get to know the patient and family. It's all right there in front of you,” Dr. Lake said.

HENDERSON, NEV. – Treating medication overuse headache involves a three-pronged approach of patient education, teaching pain coping skills, and addressing psychological issues that put patients at risk for relapse, Alvin E. Lake III, Ph.D., said at a symposium sponsored by the American Headache Society.

Most patients don't understand that excessive use of opioids can actually make them hypersensitive to pain, said Dr. Lake of the Michigan Head Pain and Neurological Institute, Ann Arbor. “They believe the pain is stronger than the medication, not that the medication is actually making them worse.” This thought process can be the root of ever-increasing medication use, as the patient experiences “pain anxiety” and attempts to forestall pain by premedicating.

The first step is to teach patients how medication overuse exacerbates headache pain, he said. Only when they have a clear understanding of this relationship will they be open to adhering to medication limits.

Sustained opioid use downregulates opioid receptors and upregulates excitatory receptors. This results in increased synthesis of excitatory neuropeptides. “Opioid tolerance is a red flag for induced abnormal pain sensitivity,” Dr. Lake said.

Overusing analgesics also interferes with effective prophylaxis, he said, citing a “seminal” 1990 study in which all patients received the same training in coping skills. Those who discontinued their daily analgesic and got a new prophylactic drug experienced the biggest improvement with their headaches.

Those who discontinued their analgesic but stayed on the same preventative improved as well, although not as much, while those who continued their daily analgesic experienced almost no improvement (Headache 1990;30:634–8).

“This study, which I use as a teaching tool, also shows patients that improvement doesn't happen immediately. They need to stay the course. It takes time for the receptors to remodulate, and how much time depends on how long they've been taking the medication and how much they've been on,” Dr. Lake said.

Simply taking away the analgesic isn't the answer, he stressed. Patients need to understand that drugs are not the only way to alleviate headaches, and that they will probably have to tolerate some level of pain. “The evidence, clinically and empirically, shows that it's very difficult for these patients to move to pain-free days. They have to find ways of dealing with headache that doesn't involve drugs.”

Biofeedback, stress management, and antidepressants all may be effective tools in relearning responses to headache pain. A 2001 study concluded that a combination of stress management and antidepressants was more effective than was either treatment alone in reducing chronic tension-type headache (JAMA 2001;285:2208–15).

And a 2002 study of medication overuse relapse showed that 3 years after medication withdrawal, patients on a combination of biofeedback and prophylactic medication experienced significantly fewer headaches per month and used less analgesic medication per month than did those on prophylaxis only (Headache 2002;42:483–90).

Treating any comorbid psychiatric disorder is critical, Dr. Lake said. His own unpublished study of 267 consecutive patients shows how common psychiatric disorders are in headache patients: All of the patients had at least one Axis I disorder, including depression (70%) and anxiety (40%). Another 26% had an Axis II personality disorder. Of those with an Axis II disorder, 63% had medication overuse headache, compared with 42% of those without such a disorder. The presence of an Axis II disorder was significantly associated with a poor long-term outcome.

Hospitalization may be the best way to assess the presence of these additional problems. “This gives you an opportunity to observe not only the patient's behavior, but family interactions and marital problems that you might not see otherwise. When they come into your office they may be able to pull it all together for a half an hour, but when you see them day in and day out, you have the opportunity to get to know the patient and family. It's all right there in front of you,” Dr. Lake said.

A new class of drugs under development for Alzheimer's disease has taken a cue from one of the world's oldest drugs–nicotine.

The highly selective nicotinic receptor agonists (NRAs) have the potential to mimic, and surpass, the cognition-enhancing effects of nicotine without its cardiovascular or addictive side effects. Tantalizing evidence suggests that the engineered molecules could provide a therapeutic one-two punch for Alzheimer's patients: immediate cognitive improvement and protection against the amyloid β plaques and neurofibrillatory tangling that are the disease's hallmarks.

Brains of patients with Alzheimer's disease (AD) show another distinct characteristic: a significant loss of cholinergic neurons and acetylcholine receptors, in addition to the hallmark plaques and tangles, said Dr. Marwan Sabbagh, a neurologist and director of the Sun Health Research Institute's Cleo Roberts Center for Clinical Research in Sun City, Ariz. “Initially, it was thought that muscarinic receptors were selectively affected in Alzheimer's, but now we think that's not so,” he explained. “It seems that the nicotinic receptors are the ones that go.”

Nicotinic acetylcholine receptors (nAChRs) are activated by acetylcholine, but they also react to nicotine and structurally similar molecules. Two types of nAChRs, the α7 and the α4-β2, are richly distributed in areas of the brain targeted by Alzheimer's. Other types of nAChRs occur in skeletal muscle and gut tissue.

Postmortem studies have shown that up to 50% of nAChRs are lost in Alzheimer's brains. This is apparently related to the buildup of amyloid β plaques, which seem to preferentially attach to the α7 nAChRs, the type most highly expressed in the hippocampus and frontal cortex, Dr. Sabbagh said in an interview. “High affinity α4-β2 receptors are preferentially lost in AD but the α7 receptor is expressed in plaques. This suggests that the biological interaction between the nicotinic receptors and AD pathology is complex,” he said.

A selective nAChR agonist could improve cholinergic function in a couple of ways, Dr. Sabbagh said. The surviving receptors would become more sensitive to any available acetylcholine. And since nAChRs help modulate the flow of other neurotransmitters, boosting their function could improve levels of dopamine, norepinephrine, and γ-amino butyric acid as well.

But since nAChRs are distributed throughout many tissues, a compound that attaches nonselectively could be loaded with adverse effects. “The challenge is to develop a selective agonist that enhances the activity of the high-affinity receptors in the brain, but not the nicotinic receptors that occur in the muscles, the gastrointestinal tract, or anywhere else.”

Drug companies are hot on the trail of such compounds. At least three agonists that target receptors involved in cognitive impairment are in preclinical or clinical trials right now. These three are described in the following paragraphs.

Targacept Inc. of Winston-Salem, N.C., a spinoff company of tobacco giant R.J. Reynolds, is farthest along the developmental pipeline with its candidate, TC-1734. In 2004, the company completed two phase II safety trials of the drug for age-associated memory impairment and mild cognitive impairment, with a total 107 patients. According to the company Web site, the drug had positive effects on cognition.

Last month, Targacept completed a second trial in 193 cognitively impaired older adults, but company representatives declined to comment for this article, saying they were constrained by the quiet period surrounding their initial public stock offering in January.

Memory Pharmaceuticals Corp. of Montvale, N.J., recently announced positive findings from its phase I trial of MEM 3454 in 48 healthy young subjects. Cognitive performance, a secondary end point of this safety trial, significantly improved in those taking 15 mg daily, said David A. Lowe, Ph.D., the company's chief scientific officer.

The trial lasted 14 days and tested three doses (15 mg, 50 mg, and 150 mg). Only the 15-mg dose showed a statistically significant effect on cognition. “One particularly interesting observation was that the effect on day 13 was stronger than it was on day 2,” Dr. Lowe said in an interview. “This shows that the effect is sustained.” The company will proceed with a phase IIa trial later this year.

Abbott Laboratories has a number of NRAs in the works, said James Sullivan, Ph.D., the company's vice president of neuroscience research. ABT-089 had proceeded to phase II trials in adults with attention-deficit hyperactivity disorder, but is now back in the preclinical stage for additional toxicologic studies. The drug also has potential as an Alzheimer's therapy, Dr. Sullivan said.

Although there are no published data on neuroprotective effects of any of the NRAs in development, studies suggest that nicotine blocks the aggregation of amyloid β on neurons. If NRAs work the same way, they might reduce or prevent neuronal plaque buildup.

But a study released last year concluded that the compounds could actually worsen the other major component of Alzheimer's pathology: neurofibrillatory tangling.

Frank LaFerla, Ph.D., and colleagues administered daily nicotine to mice genetically engineered to develop amyloid β plaques and neurofibrillatory tangling. After 5 months, their brains showed significant accumulation of tau in pyramidal neurons–a preliminary event in tangle formation–and significant increases in phosphorylated tau, a protein found in the tangles (PNAS 2005;102:3046–51).

“That doesn't mean that there isn't a place for NRAs,” said Dr. LaFerla, codirector of the Institute for Brain Aging and Dementia at the University of California, Irvine. “Nicotine is a pretty dirty drug and probably has other effects than just binding to the receptor. If you could come up with a more selective compound, you might still see a beneficial effect.”

An Alzheimer's drug that would provide quick cognitive benefits and progressive disease modification would have enormous impact, according to Dr. Peter Whitehouse. But disappointment over past efforts to enhance the cholinergic system, including today's cholinesterase inhibitors, has provoked concern about this new pharmacotherapy.

“Maybe if the cholinesterase inhibitors had worked better, we'd be seeing a different climate for NRAs,” said Dr. Whitehouse, professor of neurology at Case Western Reserve University, Cleveland. “It will be a challenge to find drugs with an effect size much larger than current cholinesterase inhibitors.”

A new class of drugs under development for Alzheimer's disease has taken a cue from one of the world's oldest drugs–nicotine.

The highly selective nicotinic receptor agonists (NRAs) have the potential to mimic, and surpass, the cognition-enhancing effects of nicotine without its cardiovascular or addictive side effects. Tantalizing evidence suggests that the engineered molecules could provide a therapeutic one-two punch for Alzheimer's patients: immediate cognitive improvement and protection against the amyloid β plaques and neurofibrillatory tangling that are the disease's hallmarks.

Brains of patients with Alzheimer's disease (AD) show another distinct characteristic: a significant loss of cholinergic neurons and acetylcholine receptors, in addition to the hallmark plaques and tangles, said Dr. Marwan Sabbagh, a neurologist and director of the Sun Health Research Institute's Cleo Roberts Center for Clinical Research in Sun City, Ariz. “Initially, it was thought that muscarinic receptors were selectively affected in Alzheimer's, but now we think that's not so,” he explained. “It seems that the nicotinic receptors are the ones that go.”

Nicotinic acetylcholine receptors (nAChRs) are activated by acetylcholine, but they also react to nicotine and structurally similar molecules. Two types of nAChRs, the α7 and the α4-β2, are richly distributed in areas of the brain targeted by Alzheimer's. Other types of nAChRs occur in skeletal muscle and gut tissue.

Postmortem studies have shown that up to 50% of nAChRs are lost in Alzheimer's brains. This is apparently related to the buildup of amyloid β plaques, which seem to preferentially attach to the α7 nAChRs, the type most highly expressed in the hippocampus and frontal cortex, Dr. Sabbagh said in an interview. “High affinity α4-β2 receptors are preferentially lost in AD but the α7 receptor is expressed in plaques. This suggests that the biological interaction between the nicotinic receptors and AD pathology is complex,” he said.

A selective nAChR agonist could improve cholinergic function in a couple of ways, Dr. Sabbagh said. The surviving receptors would become more sensitive to any available acetylcholine. And since nAChRs help modulate the flow of other neurotransmitters, boosting their function could improve levels of dopamine, norepinephrine, and γ-amino butyric acid as well.

But since nAChRs are distributed throughout many tissues, a compound that attaches nonselectively could be loaded with adverse effects. “The challenge is to develop a selective agonist that enhances the activity of the high-affinity receptors in the brain, but not the nicotinic receptors that occur in the muscles, the gastrointestinal tract, or anywhere else.”

Drug companies are hot on the trail of such compounds. At least three agonists that target receptors involved in cognitive impairment are in preclinical or clinical trials right now. These three are described in the following paragraphs.

Targacept Inc. of Winston-Salem, N.C., a spinoff company of tobacco giant R.J. Reynolds, is farthest along the developmental pipeline with its candidate, TC-1734. In 2004, the company completed two phase II safety trials of the drug for age-associated memory impairment and mild cognitive impairment, with a total 107 patients. According to the company Web site, the drug had positive effects on cognition.

Last month, Targacept completed a second trial in 193 cognitively impaired older adults, but company representatives declined to comment for this article, saying they were constrained by the quiet period surrounding their initial public stock offering in January.

Memory Pharmaceuticals Corp. of Montvale, N.J., recently announced positive findings from its phase I trial of MEM 3454 in 48 healthy young subjects. Cognitive performance, a secondary end point of this safety trial, significantly improved in those taking 15 mg daily, said David A. Lowe, Ph.D., the company's chief scientific officer.

The trial lasted 14 days and tested three doses (15 mg, 50 mg, and 150 mg). Only the 15-mg dose showed a statistically significant effect on cognition. “One particularly interesting observation was that the effect on day 13 was stronger than it was on day 2,” Dr. Lowe said in an interview. “This shows that the effect is sustained.” The company will proceed with a phase IIa trial later this year.

Abbott Laboratories has a number of NRAs in the works, said James Sullivan, Ph.D., the company's vice president of neuroscience research. ABT-089 had proceeded to phase II trials in adults with attention-deficit hyperactivity disorder, but is now back in the preclinical stage for additional toxicologic studies. The drug also has potential as an Alzheimer's therapy, Dr. Sullivan said.

Although there are no published data on neuroprotective effects of any of the NRAs in development, studies suggest that nicotine blocks the aggregation of amyloid β on neurons. If NRAs work the same way, they might reduce or prevent neuronal plaque buildup.

But a study released last year concluded that the compounds could actually worsen the other major component of Alzheimer's pathology: neurofibrillatory tangling.

Frank LaFerla, Ph.D., and colleagues administered daily nicotine to mice genetically engineered to develop amyloid β plaques and neurofibrillatory tangling. After 5 months, their brains showed significant accumulation of tau in pyramidal neurons–a preliminary event in tangle formation–and significant increases in phosphorylated tau, a protein found in the tangles (PNAS 2005;102:3046–51).

“That doesn't mean that there isn't a place for NRAs,” said Dr. LaFerla, codirector of the Institute for Brain Aging and Dementia at the University of California, Irvine. “Nicotine is a pretty dirty drug and probably has other effects than just binding to the receptor. If you could come up with a more selective compound, you might still see a beneficial effect.”

An Alzheimer's drug that would provide quick cognitive benefits and progressive disease modification would have enormous impact, according to Dr. Peter Whitehouse. But disappointment over past efforts to enhance the cholinergic system, including today's cholinesterase inhibitors, has provoked concern about this new pharmacotherapy.

“Maybe if the cholinesterase inhibitors had worked better, we'd be seeing a different climate for NRAs,” said Dr. Whitehouse, professor of neurology at Case Western Reserve University, Cleveland. “It will be a challenge to find drugs with an effect size much larger than current cholinesterase inhibitors.”

A new class of drugs under development for Alzheimer's disease has taken a cue from one of the world's oldest drugs–nicotine.

The highly selective nicotinic receptor agonists (NRAs) have the potential to mimic, and surpass, the cognition-enhancing effects of nicotine without its cardiovascular or addictive side effects. Tantalizing evidence suggests that the engineered molecules could provide a therapeutic one-two punch for Alzheimer's patients: immediate cognitive improvement and protection against the amyloid β plaques and neurofibrillatory tangling that are the disease's hallmarks.

Brains of patients with Alzheimer's disease (AD) show another distinct characteristic: a significant loss of cholinergic neurons and acetylcholine receptors, in addition to the hallmark plaques and tangles, said Dr. Marwan Sabbagh, a neurologist and director of the Sun Health Research Institute's Cleo Roberts Center for Clinical Research in Sun City, Ariz. “Initially, it was thought that muscarinic receptors were selectively affected in Alzheimer's, but now we think that's not so,” he explained. “It seems that the nicotinic receptors are the ones that go.”

Nicotinic acetylcholine receptors (nAChRs) are activated by acetylcholine, but they also react to nicotine and structurally similar molecules. Two types of nAChRs, the α7 and the α4-β2, are richly distributed in areas of the brain targeted by Alzheimer's. Other types of nAChRs occur in skeletal muscle and gut tissue.

Postmortem studies have shown that up to 50% of nAChRs are lost in Alzheimer's brains. This is apparently related to the buildup of amyloid β plaques, which seem to preferentially attach to the α7 nAChRs, the type most highly expressed in the hippocampus and frontal cortex, Dr. Sabbagh said in an interview. “High affinity α4-β2 receptors are preferentially lost in AD but the α7 receptor is expressed in plaques. This suggests that the biological interaction between the nicotinic receptors and AD pathology is complex,” he said.

A selective nAChR agonist could improve cholinergic function in a couple of ways, Dr. Sabbagh said. The surviving receptors would become more sensitive to any available acetylcholine. And since nAChRs help modulate the flow of other neurotransmitters, boosting their function could improve levels of dopamine, norepinephrine, and γ-amino butyric acid as well.

But since nAChRs are distributed throughout many tissues, a compound that attaches nonselectively could be loaded with adverse effects. “The challenge is to develop a selective agonist that enhances the activity of the high-affinity receptors in the brain, but not the nicotinic receptors that occur in the muscles, the gastrointestinal tract, or anywhere else.”

Drug companies are hot on the trail of such compounds. At least three agonists that target receptors involved in cognitive impairment are in preclinical or clinical trials right now. These three are described in the following paragraphs.

Targacept Inc. of Winston-Salem, N.C., a spinoff company of tobacco giant R.J. Reynolds, is farthest along the developmental pipeline with its candidate, TC-1734. In 2004, the company completed two phase II safety trials of the drug for age-associated memory impairment and mild cognitive impairment, with a total 107 patients. According to the company Web site, the drug had positive effects on cognition.

Last month, Targacept completed a second trial in 193 cognitively impaired older adults, but company representatives declined to comment for this article, saying they were constrained by the quiet period surrounding their initial public stock offering in January.

Memory Pharmaceuticals Corp. of Montvale, N.J., recently announced positive findings from its phase I trial of MEM 3454 in 48 healthy young subjects. Cognitive performance, a secondary end point of this safety trial, significantly improved in those taking 15 mg daily, said David A. Lowe, Ph.D., the company's chief scientific officer.

The trial lasted 14 days and tested three doses (15 mg, 50 mg, and 150 mg). Only the 15-mg dose showed a statistically significant effect on cognition. “One particularly interesting observation was that the effect on day 13 was stronger than it was on day 2,” Dr. Lowe said in an interview. “This shows that the effect is sustained.” The company will proceed with a phase IIa trial later this year.

Abbott Laboratories has a number of NRAs in the works, said James Sullivan, Ph.D., the company's vice president of neuroscience research. ABT-089 had proceeded to phase II trials in adults with attention-deficit hyperactivity disorder, but is now back in the preclinical stage for additional toxicologic studies. The drug also has potential as an Alzheimer's therapy, Dr. Sullivan said.

Although there are no published data on neuroprotective effects of any of the NRAs in development, studies suggest that nicotine blocks the aggregation of amyloid β on neurons. If NRAs work the same way, they might reduce or prevent neuronal plaque buildup.

But a study released last year concluded that the compounds could actually worsen the other major component of Alzheimer's pathology: neurofibrillatory tangling.

Frank LaFerla, Ph.D., and colleagues administered daily nicotine to mice genetically engineered to develop amyloid β plaques and neurofibrillatory tangling. After 5 months, their brains showed significant accumulation of tau in pyramidal neurons–a preliminary event in tangle formation–and significant increases in phosphorylated tau, a protein found in the tangles (PNAS 2005;102:3046–51).

“That doesn't mean that there isn't a place for NRAs,” said Dr. LaFerla, codirector of the Institute for Brain Aging and Dementia at the University of California, Irvine. “Nicotine is a pretty dirty drug and probably has other effects than just binding to the receptor. If you could come up with a more selective compound, you might still see a beneficial effect.”

An Alzheimer's drug that would provide quick cognitive benefits and progressive disease modification would have enormous impact, according to Dr. Peter Whitehouse. But disappointment over past efforts to enhance the cholinergic system, including today's cholinesterase inhibitors, has provoked concern about this new pharmacotherapy.

“Maybe if the cholinesterase inhibitors had worked better, we'd be seeing a different climate for NRAs,” said Dr. Whitehouse, professor of neurology at Case Western Reserve University, Cleveland. “It will be a challenge to find drugs with an effect size much larger than current cholinesterase inhibitors.”

The Food and Drug Administration has approved new labeling that relaxes the liver enzyme monitoring recommendations for tolcapone, an adjunctive treatment for Parkinson's disease, according to the drug's manufacturer.

The new label recommends monitoring serum glutamic-pyruvic transaminase (SGPT/ALT) and serum glutamic-oxaloacetic transaminase (SGOT/AST) at baseline, then very 2–4 weeks for the first 6 months. After that, periodic monitoring is recommended as the prescribing physician deems clinically relevant.

The drug was approved as Tasmar in January 1998 for adjunctive use in patients whose Parkinson's symptoms are not adequately controlled despite being on adequate doses of levodopa/carbidopa, according to the FDA. By October of that year, FDA had received reports of three cases of fatal fulminant liver failure; the agency said many more cases might have gone unreported. The reports prompted a black box warning on the drug label, citing an increased risk for liver failure of up to 100 times above the background population. The warning recommended liver enzyme monitoring every 2 weeks for the first year of therapy, every 4 weeks for the next 6 months, and then every 8 weeks thereafter.

However, based on a data analysis by Valeant Pharmaceuticals International, which makes the drug, FDA has concluded that the risk of liver failure is probably lower than initially estimated. The analysis included more than 40,000 patient-years of prescription data and laboratory test data from more than 3,400 patients who participated in tolcapone clinical trials.

“Recent data suggests that hepatic dysfunction associated with Tasmar is rare and can be addressed with less restrictive monitoring,” Dr. C. Warren Olanow, professor and chair of neurology at Mount Sinai School of Medicine, New York, said in a statement on the company's Web site (www.valeant.com

The new label information should show up soon on the drug's packaging, said Dan Springer, a spokesman for Valeant.

The Food and Drug Administration has approved new labeling that relaxes the liver enzyme monitoring recommendations for tolcapone, an adjunctive treatment for Parkinson's disease, according to the drug's manufacturer.

The new label recommends monitoring serum glutamic-pyruvic transaminase (SGPT/ALT) and serum glutamic-oxaloacetic transaminase (SGOT/AST) at baseline, then very 2–4 weeks for the first 6 months. After that, periodic monitoring is recommended as the prescribing physician deems clinically relevant.

The drug was approved as Tasmar in January 1998 for adjunctive use in patients whose Parkinson's symptoms are not adequately controlled despite being on adequate doses of levodopa/carbidopa, according to the FDA. By October of that year, FDA had received reports of three cases of fatal fulminant liver failure; the agency said many more cases might have gone unreported. The reports prompted a black box warning on the drug label, citing an increased risk for liver failure of up to 100 times above the background population. The warning recommended liver enzyme monitoring every 2 weeks for the first year of therapy, every 4 weeks for the next 6 months, and then every 8 weeks thereafter.

However, based on a data analysis by Valeant Pharmaceuticals International, which makes the drug, FDA has concluded that the risk of liver failure is probably lower than initially estimated. The analysis included more than 40,000 patient-years of prescription data and laboratory test data from more than 3,400 patients who participated in tolcapone clinical trials.

“Recent data suggests that hepatic dysfunction associated with Tasmar is rare and can be addressed with less restrictive monitoring,” Dr. C. Warren Olanow, professor and chair of neurology at Mount Sinai School of Medicine, New York, said in a statement on the company's Web site (www.valeant.com

The new label information should show up soon on the drug's packaging, said Dan Springer, a spokesman for Valeant.

The Food and Drug Administration has approved new labeling that relaxes the liver enzyme monitoring recommendations for tolcapone, an adjunctive treatment for Parkinson's disease, according to the drug's manufacturer.

The new label recommends monitoring serum glutamic-pyruvic transaminase (SGPT/ALT) and serum glutamic-oxaloacetic transaminase (SGOT/AST) at baseline, then very 2–4 weeks for the first 6 months. After that, periodic monitoring is recommended as the prescribing physician deems clinically relevant.

The drug was approved as Tasmar in January 1998 for adjunctive use in patients whose Parkinson's symptoms are not adequately controlled despite being on adequate doses of levodopa/carbidopa, according to the FDA. By October of that year, FDA had received reports of three cases of fatal fulminant liver failure; the agency said many more cases might have gone unreported. The reports prompted a black box warning on the drug label, citing an increased risk for liver failure of up to 100 times above the background population. The warning recommended liver enzyme monitoring every 2 weeks for the first year of therapy, every 4 weeks for the next 6 months, and then every 8 weeks thereafter.

However, based on a data analysis by Valeant Pharmaceuticals International, which makes the drug, FDA has concluded that the risk of liver failure is probably lower than initially estimated. The analysis included more than 40,000 patient-years of prescription data and laboratory test data from more than 3,400 patients who participated in tolcapone clinical trials.

“Recent data suggests that hepatic dysfunction associated with Tasmar is rare and can be addressed with less restrictive monitoring,” Dr. C. Warren Olanow, professor and chair of neurology at Mount Sinai School of Medicine, New York, said in a statement on the company's Web site (www.valeant.com

The new label information should show up soon on the drug's packaging, said Dan Springer, a spokesman for Valeant.

TORONTO — A sudden, severe onset of childhood obsessive-compulsive disorder with tics should prompt a throat culture for group A streptococcus, Dr. Tanya Murphy said at the joint annual meeting of the American Academy of Child and Adolescent Psychiatry and the Canadian Academy of Child and Adolescent Psychiatry.

Considerable controversy surrounding the issue persists. But enough evidence exists to suggest a link between acute strep infections and the onset of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), said Dr. Murphy, director of the Child Tic and Anxiety Disorder Clinic, University of Florida, Gainesville.

The OCD that children develop with a strep infection looks quite different from the chronic course usually observed. “The onset is sudden and dramatic,” she said. “The illness follows an episodic or sawtooth course that's marked by changes in strep titers. During exacerbations, you will see a positive culture or rising titers, and during prolonged remission, the titers will fall.” The OCD is often accompanied by choreiform movements, tics, and comorbid symptoms, including emotional lability, separation anxiety, nocturnal enuresis, and change in school performance.

Some children with PANDAS may not have a positive strep throat culture, however. In these cases, serial strep titers may give evidence of a subclinical infection. If strep is present, children should take a full course of antibiotics and return for a repeat culture shortly after the antibiotic is completed.

PANDAS appears to be at the center of a convergence of three factors, Dr. Murphy said: a group A strep infection, genetic predisposition (familial OCD, Tourette's syndrome, or rheumatoid fever, including Sydenham's chorea), and an environmental stress factor such as a central nervous system injury or coinfection. The incidence peaks at ages 5–12 years—the same ages in which strep infections peak.

Dr. Murphy presented the results of a prospective study of 25 children, aged 7–17 years, with typical OCD and tics. The children were assessed every 6 weeks and had at least six consecutive assessments; strep titers were taken at each visit. Fifteen children exhibited an episodic or sawtooth disease course. Almost 60% of the episodic group had elevated group A strep titers on all of their visits, while 60% of the steady disease course group had no elevated titers at any time, suggesting that those with a PANDAS-like course have had more frequent undetected strep infections or prolonged immune reaction to past infections.

Those with episodic disease were also more likely to have exacerbations in the fall and winter, concurrent with the seasonal rise in strep infections. The children in the episodic group were more likely to be male (67% vs. 30%) and have attention-deficit hyperactivity disorder (73% vs. 40%), compared with those in the steady course group.

“Unlike its namesake, however, PANDAS isn't all black and white,” Dr. Murphy said. There have been few reports that antibiotics for children suspected of having the disorder improved their OCD or tic symptoms. Definitive studies still need to be conducted to clarify the impact of antibiotic treatment on symptoms.

In a 2005 study, 23 children with PANDAS received either azithromycin or penicillin prophylaxis. The drugs decreased additional strep infections and neuropsychiatric symptom exacerbations (Biol. Psychiatry 2005;57:788–92).

In 2002, a prospective study found that children with PANDAS experienced OCD symptom resolution after receiving antibiotics at the sentinel OCD episode (Arch. Pediatr. Adolesc. Med. 2002;156:356–61).

An early clinical trial involving the use of prophylactic penicillin for PANDAS revealed no conclusive evidence that the antibiotic reduced clinical exacerbation. However, the sample size was small (37 subjects), the treatment arm was brief, and the lack of efficacy may have been attributable to the failure of antibiotic therapy to eliminate streptococcal colonization in the patients enrolled in the study, Dr. Murphy said. Since then, investigators have reported improvement in neuropsychiatric symptoms with antibiotic treatment in patients presenting with PANDAS. Difficulties with study design and the small sample size of these early antibiotic trials limit the clinical influence of their findings.

TORONTO — A sudden, severe onset of childhood obsessive-compulsive disorder with tics should prompt a throat culture for group A streptococcus, Dr. Tanya Murphy said at the joint annual meeting of the American Academy of Child and Adolescent Psychiatry and the Canadian Academy of Child and Adolescent Psychiatry.

Considerable controversy surrounding the issue persists. But enough evidence exists to suggest a link between acute strep infections and the onset of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), said Dr. Murphy, director of the Child Tic and Anxiety Disorder Clinic, University of Florida, Gainesville.

The OCD that children develop with a strep infection looks quite different from the chronic course usually observed. “The onset is sudden and dramatic,” she said. “The illness follows an episodic or sawtooth course that's marked by changes in strep titers. During exacerbations, you will see a positive culture or rising titers, and during prolonged remission, the titers will fall.” The OCD is often accompanied by choreiform movements, tics, and comorbid symptoms, including emotional lability, separation anxiety, nocturnal enuresis, and change in school performance.

Some children with PANDAS may not have a positive strep throat culture, however. In these cases, serial strep titers may give evidence of a subclinical infection. If strep is present, children should take a full course of antibiotics and return for a repeat culture shortly after the antibiotic is completed.

PANDAS appears to be at the center of a convergence of three factors, Dr. Murphy said: a group A strep infection, genetic predisposition (familial OCD, Tourette's syndrome, or rheumatoid fever, including Sydenham's chorea), and an environmental stress factor such as a central nervous system injury or coinfection. The incidence peaks at ages 5–12 years—the same ages in which strep infections peak.

Dr. Murphy presented the results of a prospective study of 25 children, aged 7–17 years, with typical OCD and tics. The children were assessed every 6 weeks and had at least six consecutive assessments; strep titers were taken at each visit. Fifteen children exhibited an episodic or sawtooth disease course. Almost 60% of the episodic group had elevated group A strep titers on all of their visits, while 60% of the steady disease course group had no elevated titers at any time, suggesting that those with a PANDAS-like course have had more frequent undetected strep infections or prolonged immune reaction to past infections.

Those with episodic disease were also more likely to have exacerbations in the fall and winter, concurrent with the seasonal rise in strep infections. The children in the episodic group were more likely to be male (67% vs. 30%) and have attention-deficit hyperactivity disorder (73% vs. 40%), compared with those in the steady course group.

“Unlike its namesake, however, PANDAS isn't all black and white,” Dr. Murphy said. There have been few reports that antibiotics for children suspected of having the disorder improved their OCD or tic symptoms. Definitive studies still need to be conducted to clarify the impact of antibiotic treatment on symptoms.

In a 2005 study, 23 children with PANDAS received either azithromycin or penicillin prophylaxis. The drugs decreased additional strep infections and neuropsychiatric symptom exacerbations (Biol. Psychiatry 2005;57:788–92).

In 2002, a prospective study found that children with PANDAS experienced OCD symptom resolution after receiving antibiotics at the sentinel OCD episode (Arch. Pediatr. Adolesc. Med. 2002;156:356–61).

An early clinical trial involving the use of prophylactic penicillin for PANDAS revealed no conclusive evidence that the antibiotic reduced clinical exacerbation. However, the sample size was small (37 subjects), the treatment arm was brief, and the lack of efficacy may have been attributable to the failure of antibiotic therapy to eliminate streptococcal colonization in the patients enrolled in the study, Dr. Murphy said. Since then, investigators have reported improvement in neuropsychiatric symptoms with antibiotic treatment in patients presenting with PANDAS. Difficulties with study design and the small sample size of these early antibiotic trials limit the clinical influence of their findings.

TORONTO — A sudden, severe onset of childhood obsessive-compulsive disorder with tics should prompt a throat culture for group A streptococcus, Dr. Tanya Murphy said at the joint annual meeting of the American Academy of Child and Adolescent Psychiatry and the Canadian Academy of Child and Adolescent Psychiatry.

Considerable controversy surrounding the issue persists. But enough evidence exists to suggest a link between acute strep infections and the onset of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), said Dr. Murphy, director of the Child Tic and Anxiety Disorder Clinic, University of Florida, Gainesville.

The OCD that children develop with a strep infection looks quite different from the chronic course usually observed. “The onset is sudden and dramatic,” she said. “The illness follows an episodic or sawtooth course that's marked by changes in strep titers. During exacerbations, you will see a positive culture or rising titers, and during prolonged remission, the titers will fall.” The OCD is often accompanied by choreiform movements, tics, and comorbid symptoms, including emotional lability, separation anxiety, nocturnal enuresis, and change in school performance.

Some children with PANDAS may not have a positive strep throat culture, however. In these cases, serial strep titers may give evidence of a subclinical infection. If strep is present, children should take a full course of antibiotics and return for a repeat culture shortly after the antibiotic is completed.

PANDAS appears to be at the center of a convergence of three factors, Dr. Murphy said: a group A strep infection, genetic predisposition (familial OCD, Tourette's syndrome, or rheumatoid fever, including Sydenham's chorea), and an environmental stress factor such as a central nervous system injury or coinfection. The incidence peaks at ages 5–12 years—the same ages in which strep infections peak.

Dr. Murphy presented the results of a prospective study of 25 children, aged 7–17 years, with typical OCD and tics. The children were assessed every 6 weeks and had at least six consecutive assessments; strep titers were taken at each visit. Fifteen children exhibited an episodic or sawtooth disease course. Almost 60% of the episodic group had elevated group A strep titers on all of their visits, while 60% of the steady disease course group had no elevated titers at any time, suggesting that those with a PANDAS-like course have had more frequent undetected strep infections or prolonged immune reaction to past infections.

Those with episodic disease were also more likely to have exacerbations in the fall and winter, concurrent with the seasonal rise in strep infections. The children in the episodic group were more likely to be male (67% vs. 30%) and have attention-deficit hyperactivity disorder (73% vs. 40%), compared with those in the steady course group.

“Unlike its namesake, however, PANDAS isn't all black and white,” Dr. Murphy said. There have been few reports that antibiotics for children suspected of having the disorder improved their OCD or tic symptoms. Definitive studies still need to be conducted to clarify the impact of antibiotic treatment on symptoms.

In a 2005 study, 23 children with PANDAS received either azithromycin or penicillin prophylaxis. The drugs decreased additional strep infections and neuropsychiatric symptom exacerbations (Biol. Psychiatry 2005;57:788–92).

In 2002, a prospective study found that children with PANDAS experienced OCD symptom resolution after receiving antibiotics at the sentinel OCD episode (Arch. Pediatr. Adolesc. Med. 2002;156:356–61).

An early clinical trial involving the use of prophylactic penicillin for PANDAS revealed no conclusive evidence that the antibiotic reduced clinical exacerbation. However, the sample size was small (37 subjects), the treatment arm was brief, and the lack of efficacy may have been attributable to the failure of antibiotic therapy to eliminate streptococcal colonization in the patients enrolled in the study, Dr. Murphy said. Since then, investigators have reported improvement in neuropsychiatric symptoms with antibiotic treatment in patients presenting with PANDAS. Difficulties with study design and the small sample size of these early antibiotic trials limit the clinical influence of their findings.

KISSIMMEE, FLA. — A combination of intravenous and intraarterial thrombolysis significantly improved outcomes in stroke patients whose clots did not clear with initial thrombolytic therapy, Dr. Joseph Broderick reported at the 31st International Stroke Conference.

“We already know that tissue plasminogen activator (TPA) is an effective drug, but it doesn't open the artery in every patient,” Dr. Broderick, chairman of the neurology department at the University of Cincinnati, said in an interview. “We need another way to help these people.”

The Interventional Management of Stroke Study-II (IMS-II) included 73 patients with severe stroke (median National Institutes of Health Stroke Scale score of 19). All received an initial course of low-dose intravenous TPA within the first 3 hours of stroke onset (median time 41 minutes).

The initial thrombolysis cleared the clot in 22 patients, none of whom received further therapy. The remaining 51 patients, however, still had a clot blocking an artery in either the neck or the head.

Those patients were treated with an additional dose of TPA (maximum 22 mg). In 33 patients, the drug was delivered directly to the clot by an infusion catheter equipped with a low-dose ultrasound transducer at the distal tip. The ultrasound energy creates microfractures in the clot, which enables the better delivery of the thrombolytic agent.

The remaining 18 patients received the additional therapy with a standard catheter.

Dr. Broderick compared outcomes in the 51 patients who received the intraarterial therapy with those of patients matched for age and stroke severity who received intravenous recombinant TPA in a 1995 study called the National Institute of Neurological Disorders and Stroke (NINDS) rtPA [recombinant tissue-type plasminogen activator] Stroke Study Group (N. Engl. J. Med. 1995;333:1581–8).

The patients in the IMS-II study had significantly lower mortality at 3 months (16% vs. 21%), and more of them had a Rankin score of 0–2 at 3 months (45% vs. 39%; odds ratio 1.65), compared with the NINDS study patients.

Symptomatic intracranial bleeds occurred more frequently in the IMS-II group than in the NINDS group (11% vs. 6.6%), as did asymptomatic bleeds (29% vs. 6%). This is not surprising, given that the invasive nature of the second course of TPA, Dr. Broderick said at the conference, which was sponsored by the American Stroke Association.

The increased risk of bleeding indicates that intraarterial therapy should be reserved for those patients with severe stroke. Older patients should be carefully evaluated before receiving the treatment, he warned.

The IMS-II trial didn't distinguish the effect of the interventional device versus the thrombolytic drug, Dr. Broderick noted. “We weren't testing an individual device; we were testing a therapeutic approach.”

A third IMS trial, sponsored by NINDS, is designed to evaluate the combined thrombolytic approach using a number of different devices. Physicians will be allowed to use any FDA-approved clot removal device; if additional devices are approved during the course of the trial, they will be allowed.

The treatment advantage of this trial design is clear, Dr. Broderick noted.

“There's no one choice that is good for all clots. Physicians will get to choose the right tool for the job. The important thing is to maximize the quickest possible opening of the blocked artery,” he said.

He hopes to include 50 centers and 900 patients in the new trial.

'The important thing is to maximize the quickest possible opening of the blocked artery.' DR. BRODERICK

KISSIMMEE, FLA. — A combination of intravenous and intraarterial thrombolysis significantly improved outcomes in stroke patients whose clots did not clear with initial thrombolytic therapy, Dr. Joseph Broderick reported at the 31st International Stroke Conference.

“We already know that tissue plasminogen activator (TPA) is an effective drug, but it doesn't open the artery in every patient,” Dr. Broderick, chairman of the neurology department at the University of Cincinnati, said in an interview. “We need another way to help these people.”

The Interventional Management of Stroke Study-II (IMS-II) included 73 patients with severe stroke (median National Institutes of Health Stroke Scale score of 19). All received an initial course of low-dose intravenous TPA within the first 3 hours of stroke onset (median time 41 minutes).

The initial thrombolysis cleared the clot in 22 patients, none of whom received further therapy. The remaining 51 patients, however, still had a clot blocking an artery in either the neck or the head.

Those patients were treated with an additional dose of TPA (maximum 22 mg). In 33 patients, the drug was delivered directly to the clot by an infusion catheter equipped with a low-dose ultrasound transducer at the distal tip. The ultrasound energy creates microfractures in the clot, which enables the better delivery of the thrombolytic agent.

The remaining 18 patients received the additional therapy with a standard catheter.

Dr. Broderick compared outcomes in the 51 patients who received the intraarterial therapy with those of patients matched for age and stroke severity who received intravenous recombinant TPA in a 1995 study called the National Institute of Neurological Disorders and Stroke (NINDS) rtPA [recombinant tissue-type plasminogen activator] Stroke Study Group (N. Engl. J. Med. 1995;333:1581–8).

The patients in the IMS-II study had significantly lower mortality at 3 months (16% vs. 21%), and more of them had a Rankin score of 0–2 at 3 months (45% vs. 39%; odds ratio 1.65), compared with the NINDS study patients.

Symptomatic intracranial bleeds occurred more frequently in the IMS-II group than in the NINDS group (11% vs. 6.6%), as did asymptomatic bleeds (29% vs. 6%). This is not surprising, given that the invasive nature of the second course of TPA, Dr. Broderick said at the conference, which was sponsored by the American Stroke Association.

The increased risk of bleeding indicates that intraarterial therapy should be reserved for those patients with severe stroke. Older patients should be carefully evaluated before receiving the treatment, he warned.

The IMS-II trial didn't distinguish the effect of the interventional device versus the thrombolytic drug, Dr. Broderick noted. “We weren't testing an individual device; we were testing a therapeutic approach.”

A third IMS trial, sponsored by NINDS, is designed to evaluate the combined thrombolytic approach using a number of different devices. Physicians will be allowed to use any FDA-approved clot removal device; if additional devices are approved during the course of the trial, they will be allowed.

The treatment advantage of this trial design is clear, Dr. Broderick noted.

“There's no one choice that is good for all clots. Physicians will get to choose the right tool for the job. The important thing is to maximize the quickest possible opening of the blocked artery,” he said.

He hopes to include 50 centers and 900 patients in the new trial.

'The important thing is to maximize the quickest possible opening of the blocked artery.' DR. BRODERICK

KISSIMMEE, FLA. — A combination of intravenous and intraarterial thrombolysis significantly improved outcomes in stroke patients whose clots did not clear with initial thrombolytic therapy, Dr. Joseph Broderick reported at the 31st International Stroke Conference.

“We already know that tissue plasminogen activator (TPA) is an effective drug, but it doesn't open the artery in every patient,” Dr. Broderick, chairman of the neurology department at the University of Cincinnati, said in an interview. “We need another way to help these people.”

The Interventional Management of Stroke Study-II (IMS-II) included 73 patients with severe stroke (median National Institutes of Health Stroke Scale score of 19). All received an initial course of low-dose intravenous TPA within the first 3 hours of stroke onset (median time 41 minutes).

The initial thrombolysis cleared the clot in 22 patients, none of whom received further therapy. The remaining 51 patients, however, still had a clot blocking an artery in either the neck or the head.

Those patients were treated with an additional dose of TPA (maximum 22 mg). In 33 patients, the drug was delivered directly to the clot by an infusion catheter equipped with a low-dose ultrasound transducer at the distal tip. The ultrasound energy creates microfractures in the clot, which enables the better delivery of the thrombolytic agent.

The remaining 18 patients received the additional therapy with a standard catheter.

Dr. Broderick compared outcomes in the 51 patients who received the intraarterial therapy with those of patients matched for age and stroke severity who received intravenous recombinant TPA in a 1995 study called the National Institute of Neurological Disorders and Stroke (NINDS) rtPA [recombinant tissue-type plasminogen activator] Stroke Study Group (N. Engl. J. Med. 1995;333:1581–8).

The patients in the IMS-II study had significantly lower mortality at 3 months (16% vs. 21%), and more of them had a Rankin score of 0–2 at 3 months (45% vs. 39%; odds ratio 1.65), compared with the NINDS study patients.

Symptomatic intracranial bleeds occurred more frequently in the IMS-II group than in the NINDS group (11% vs. 6.6%), as did asymptomatic bleeds (29% vs. 6%). This is not surprising, given that the invasive nature of the second course of TPA, Dr. Broderick said at the conference, which was sponsored by the American Stroke Association.

The increased risk of bleeding indicates that intraarterial therapy should be reserved for those patients with severe stroke. Older patients should be carefully evaluated before receiving the treatment, he warned.

The IMS-II trial didn't distinguish the effect of the interventional device versus the thrombolytic drug, Dr. Broderick noted. “We weren't testing an individual device; we were testing a therapeutic approach.”

A third IMS trial, sponsored by NINDS, is designed to evaluate the combined thrombolytic approach using a number of different devices. Physicians will be allowed to use any FDA-approved clot removal device; if additional devices are approved during the course of the trial, they will be allowed.

The treatment advantage of this trial design is clear, Dr. Broderick noted.

“There's no one choice that is good for all clots. Physicians will get to choose the right tool for the job. The important thing is to maximize the quickest possible opening of the blocked artery,” he said.

He hopes to include 50 centers and 900 patients in the new trial.

'The important thing is to maximize the quickest possible opening of the blocked artery.' DR. BRODERICK

KISSIMMEE, FLA. — Stroke patients who take statins should continue to do so during their acute stroke treatment, because withdrawing the drugs for as brief a time as 3 days is associated with significant worsening of neurologic outcomes, researchers said at the 31st International Stroke Conference.

“Statins have not been considered essential drugs that must be continued when a patient is hospitalized for stroke,” Dr. Florentio Nombela commented in an interview.

“When stroke patients can't swallow, or when we are trying to simplify their medication routines during this time, we often discontinue the statins just to make things easier. Our study shows that this should not be done.”

Dr. Nombela of the Hospital Universitario de la Princesa, Madrid, examined statin withdrawal in 89 ischemic stroke patients. During the first 3 days after admission, statins were withdrawn from 46 patients and continued in 43 patients. All patients began atorvastatin 20 mg/day on day 4 of admission.

Patients from whom statin therapy was withdrawn were nine times more likely than patients who continued on statins to experience early neurologic deterioration (a decrease of at least 4 points on their National Institutes of Health Stroke Scale score).

Early deterioration occurred in 65% of the withdrawal group (30 patients) and 21% of those in the continued therapy group (9 patients).

Upon imaging during days 4–7, patients in the withdrawal group had larger brain infarcts than those in the continued therapy group (74 cm

The withdrawal patients were 3.5 times more likely to have poor functional outcome (modified Rankin Scale score of 2 or higher) at 3 months. In the withdrawal group, 59% had poor functional outcome, compared with 37% of those in the continued therapy group.

Norinna Allen, who is a doctoral student at Yale University, New Haven, Conn., noted that use of lipid-lowering agents may provide some mortality protection when they are administered during the acute phase of stroke treatment, although there is a lack of prospective data to confirm this finding.

Her retrospective chart review included 1,256 patients admitted for ischemic stroke at 32 academic medical centers. Of the group, 41% received a statin during their stroke hospitalization and the rest did not, noted Ms. Allen, who was discussing her findings in an interview at the meeting sponsored by the American Stroke Association.

The chart review indicated only the dispensing of a statin, Ms. Allen pointed out; it did not differentiate between an existing prescription and a new prescription.

Patients who were on statins had a significantly lower rate of in-hospital mortality (1% vs. 5%). In a multivariate analysis, statin use was associated with an 80% decrease in mortality.

There was a trend toward better long-term functional outcomes, Ms. Allen said. Among those who received a statin, 58% were discharged to home (indicative of a good outcome), compared with 53% of those who didn't get a statin.

“This suggests an important relationship may be occurring, but what is exactly happening is very unclear right now,” she said.

“Recent studies do suggest that statins confer a mortality benefit in heart disease patients, beyond their ability to lower lipids,” she noted.

Dr. Nombela noted that research findings have suggested that statins have a profound effect on endothelial function. When the drugs are withdrawn, the levels of nitric oxide drop to below baseline, which causes endothelial dysfunction. The drugs also exert an anti-inflammatory effect that disappears when they are withdrawn.

Patients in the statin withdrawal group had larger brain infarcts than did those in the continued therapy group. DR. NOMBELA

KISSIMMEE, FLA. — Stroke patients who take statins should continue to do so during their acute stroke treatment, because withdrawing the drugs for as brief a time as 3 days is associated with significant worsening of neurologic outcomes, researchers said at the 31st International Stroke Conference.

“Statins have not been considered essential drugs that must be continued when a patient is hospitalized for stroke,” Dr. Florentio Nombela commented in an interview.

“When stroke patients can't swallow, or when we are trying to simplify their medication routines during this time, we often discontinue the statins just to make things easier. Our study shows that this should not be done.”

Dr. Nombela of the Hospital Universitario de la Princesa, Madrid, examined statin withdrawal in 89 ischemic stroke patients. During the first 3 days after admission, statins were withdrawn from 46 patients and continued in 43 patients. All patients began atorvastatin 20 mg/day on day 4 of admission.

Patients from whom statin therapy was withdrawn were nine times more likely than patients who continued on statins to experience early neurologic deterioration (a decrease of at least 4 points on their National Institutes of Health Stroke Scale score).

Early deterioration occurred in 65% of the withdrawal group (30 patients) and 21% of those in the continued therapy group (9 patients).

Upon imaging during days 4–7, patients in the withdrawal group had larger brain infarcts than those in the continued therapy group (74 cm

The withdrawal patients were 3.5 times more likely to have poor functional outcome (modified Rankin Scale score of 2 or higher) at 3 months. In the withdrawal group, 59% had poor functional outcome, compared with 37% of those in the continued therapy group.

Norinna Allen, who is a doctoral student at Yale University, New Haven, Conn., noted that use of lipid-lowering agents may provide some mortality protection when they are administered during the acute phase of stroke treatment, although there is a lack of prospective data to confirm this finding.

Her retrospective chart review included 1,256 patients admitted for ischemic stroke at 32 academic medical centers. Of the group, 41% received a statin during their stroke hospitalization and the rest did not, noted Ms. Allen, who was discussing her findings in an interview at the meeting sponsored by the American Stroke Association.

The chart review indicated only the dispensing of a statin, Ms. Allen pointed out; it did not differentiate between an existing prescription and a new prescription.

Patients who were on statins had a significantly lower rate of in-hospital mortality (1% vs. 5%). In a multivariate analysis, statin use was associated with an 80% decrease in mortality.

There was a trend toward better long-term functional outcomes, Ms. Allen said. Among those who received a statin, 58% were discharged to home (indicative of a good outcome), compared with 53% of those who didn't get a statin.

“This suggests an important relationship may be occurring, but what is exactly happening is very unclear right now,” she said.

“Recent studies do suggest that statins confer a mortality benefit in heart disease patients, beyond their ability to lower lipids,” she noted.

Dr. Nombela noted that research findings have suggested that statins have a profound effect on endothelial function. When the drugs are withdrawn, the levels of nitric oxide drop to below baseline, which causes endothelial dysfunction. The drugs also exert an anti-inflammatory effect that disappears when they are withdrawn.

Patients in the statin withdrawal group had larger brain infarcts than did those in the continued therapy group. DR. NOMBELA

KISSIMMEE, FLA. — Stroke patients who take statins should continue to do so during their acute stroke treatment, because withdrawing the drugs for as brief a time as 3 days is associated with significant worsening of neurologic outcomes, researchers said at the 31st International Stroke Conference.

“Statins have not been considered essential drugs that must be continued when a patient is hospitalized for stroke,” Dr. Florentio Nombela commented in an interview.

“When stroke patients can't swallow, or when we are trying to simplify their medication routines during this time, we often discontinue the statins just to make things easier. Our study shows that this should not be done.”

Dr. Nombela of the Hospital Universitario de la Princesa, Madrid, examined statin withdrawal in 89 ischemic stroke patients. During the first 3 days after admission, statins were withdrawn from 46 patients and continued in 43 patients. All patients began atorvastatin 20 mg/day on day 4 of admission.

Patients from whom statin therapy was withdrawn were nine times more likely than patients who continued on statins to experience early neurologic deterioration (a decrease of at least 4 points on their National Institutes of Health Stroke Scale score).

Early deterioration occurred in 65% of the withdrawal group (30 patients) and 21% of those in the continued therapy group (9 patients).

Upon imaging during days 4–7, patients in the withdrawal group had larger brain infarcts than those in the continued therapy group (74 cm

The withdrawal patients were 3.5 times more likely to have poor functional outcome (modified Rankin Scale score of 2 or higher) at 3 months. In the withdrawal group, 59% had poor functional outcome, compared with 37% of those in the continued therapy group.

Norinna Allen, who is a doctoral student at Yale University, New Haven, Conn., noted that use of lipid-lowering agents may provide some mortality protection when they are administered during the acute phase of stroke treatment, although there is a lack of prospective data to confirm this finding.

Her retrospective chart review included 1,256 patients admitted for ischemic stroke at 32 academic medical centers. Of the group, 41% received a statin during their stroke hospitalization and the rest did not, noted Ms. Allen, who was discussing her findings in an interview at the meeting sponsored by the American Stroke Association.

The chart review indicated only the dispensing of a statin, Ms. Allen pointed out; it did not differentiate between an existing prescription and a new prescription.

Patients who were on statins had a significantly lower rate of in-hospital mortality (1% vs. 5%). In a multivariate analysis, statin use was associated with an 80% decrease in mortality.

There was a trend toward better long-term functional outcomes, Ms. Allen said. Among those who received a statin, 58% were discharged to home (indicative of a good outcome), compared with 53% of those who didn't get a statin.

“This suggests an important relationship may be occurring, but what is exactly happening is very unclear right now,” she said.

“Recent studies do suggest that statins confer a mortality benefit in heart disease patients, beyond their ability to lower lipids,” she noted.

Dr. Nombela noted that research findings have suggested that statins have a profound effect on endothelial function. When the drugs are withdrawn, the levels of nitric oxide drop to below baseline, which causes endothelial dysfunction. The drugs also exert an anti-inflammatory effect that disappears when they are withdrawn.

Patients in the statin withdrawal group had larger brain infarcts than did those in the continued therapy group. DR. NOMBELA

MIAMI BEACH — Adenotonsillectomy in children with asthma is associated with a significant improvement in their symptoms, Dr. David E. Karas reported in a poster presented at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

All of the children in Dr. Karas' prospective study received their surgery for usual indications, including chronic tonsillitis and obstructive sleep apnea. Nevertheless, by 1 year after their surgery, Dr. Karas said in an interview, many experienced significant decreases both in medication use and asthma severity, while their parents reported missing many fewer days of work to care for children during asthma exacerbations.

“We're not saying get a tonsillectomy if you have asthma,” said Dr. Karas, a pediatric otolaryngologist at Yale University, New Haven, Conn. “But it's clear that the surgery improves upper respiratory congestion and chronic sinusitis. When the upper airway is not doing well, that eventually takes a toll on the lower airway, and when we treat the upper airway, the lower airway can improve.”

He enrolled 31 patients aged 2–12 years who underwent adenoidectomy and/or tonsillectomy and had a diagnosis of asthma. Before the surgery, each caregiver filled out a questionnaire asking about medication use, asthma severity, and school and work days missed because of asthma exacerbation. Caregivers were contacted a mean of 1 year later and asked the same questions.

Medication use dropped significantly after surgery. The number of patients using inhaled steroids decreased from 25 to 14, albuterol from 30 to 18, and leukotriene moderators from 16 to 11. The single patient who was taking a long-acting β₂-agonist before surgery was no longer taking it afterward.

The use of systemic steroids decreased as well. Before surgery, 22 patients used the drugs at least once a year; 8 required one course, 5 required two courses, 3 required three courses, and 6 required four courses. After surgery, only eight patients were using systemic steroids; all required one or two courses.

Caregivers also reported an average decrease from 2.0 to 0.81 in asthma severity symptom scores. All classes of asthma severity decreased: The number of children with severe persistent asthma declined from 4 to 0, with moderate persistent from 6 to 2, with mild persistent from 7 to 3, and with mild intermittent from 14 to 13. At the 1-year follow-up, 13 caregivers reported that their child had no asthma symptoms at all.

Of those children who attended school, the average number of missed school days per year decreased from 12.5 to 6. Caregivers' missed work days decreased as well, from 13 to 2 per year.

The relationship between upper airway infection and lower airway dysfunction may explain why some children with asthma experience exacerbations during winter and fall, when upper respiratory infections are more common, and why their symptoms improve with both oral corticosteroids and antibiotics, Dr. Karas said. “There's nothing that shrinks the tonsils like steroids—it's like you're giving a temporary medical tonsillectomy. And antibiotics treat the infective component by preventing those infected secretions that might be micro-aspirated and start up a reactive airway process.”

'We're not saying get a tonsillectomy if you have asthma.' But it's clear that it improves congestion. DR. KARAS

MIAMI BEACH — Adenotonsillectomy in children with asthma is associated with a significant improvement in their symptoms, Dr. David E. Karas reported in a poster presented at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

All of the children in Dr. Karas' prospective study received their surgery for usual indications, including chronic tonsillitis and obstructive sleep apnea. Nevertheless, by 1 year after their surgery, Dr. Karas said in an interview, many experienced significant decreases both in medication use and asthma severity, while their parents reported missing many fewer days of work to care for children during asthma exacerbations.

“We're not saying get a tonsillectomy if you have asthma,” said Dr. Karas, a pediatric otolaryngologist at Yale University, New Haven, Conn. “But it's clear that the surgery improves upper respiratory congestion and chronic sinusitis. When the upper airway is not doing well, that eventually takes a toll on the lower airway, and when we treat the upper airway, the lower airway can improve.”

He enrolled 31 patients aged 2–12 years who underwent adenoidectomy and/or tonsillectomy and had a diagnosis of asthma. Before the surgery, each caregiver filled out a questionnaire asking about medication use, asthma severity, and school and work days missed because of asthma exacerbation. Caregivers were contacted a mean of 1 year later and asked the same questions.

Medication use dropped significantly after surgery. The number of patients using inhaled steroids decreased from 25 to 14, albuterol from 30 to 18, and leukotriene moderators from 16 to 11. The single patient who was taking a long-acting β₂-agonist before surgery was no longer taking it afterward.

The use of systemic steroids decreased as well. Before surgery, 22 patients used the drugs at least once a year; 8 required one course, 5 required two courses, 3 required three courses, and 6 required four courses. After surgery, only eight patients were using systemic steroids; all required one or two courses.

Caregivers also reported an average decrease from 2.0 to 0.81 in asthma severity symptom scores. All classes of asthma severity decreased: The number of children with severe persistent asthma declined from 4 to 0, with moderate persistent from 6 to 2, with mild persistent from 7 to 3, and with mild intermittent from 14 to 13. At the 1-year follow-up, 13 caregivers reported that their child had no asthma symptoms at all.

Of those children who attended school, the average number of missed school days per year decreased from 12.5 to 6. Caregivers' missed work days decreased as well, from 13 to 2 per year.

The relationship between upper airway infection and lower airway dysfunction may explain why some children with asthma experience exacerbations during winter and fall, when upper respiratory infections are more common, and why their symptoms improve with both oral corticosteroids and antibiotics, Dr. Karas said. “There's nothing that shrinks the tonsils like steroids—it's like you're giving a temporary medical tonsillectomy. And antibiotics treat the infective component by preventing those infected secretions that might be micro-aspirated and start up a reactive airway process.”

'We're not saying get a tonsillectomy if you have asthma.' But it's clear that it improves congestion. DR. KARAS

MIAMI BEACH — Adenotonsillectomy in children with asthma is associated with a significant improvement in their symptoms, Dr. David E. Karas reported in a poster presented at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

All of the children in Dr. Karas' prospective study received their surgery for usual indications, including chronic tonsillitis and obstructive sleep apnea. Nevertheless, by 1 year after their surgery, Dr. Karas said in an interview, many experienced significant decreases both in medication use and asthma severity, while their parents reported missing many fewer days of work to care for children during asthma exacerbations.

“We're not saying get a tonsillectomy if you have asthma,” said Dr. Karas, a pediatric otolaryngologist at Yale University, New Haven, Conn. “But it's clear that the surgery improves upper respiratory congestion and chronic sinusitis. When the upper airway is not doing well, that eventually takes a toll on the lower airway, and when we treat the upper airway, the lower airway can improve.”

He enrolled 31 patients aged 2–12 years who underwent adenoidectomy and/or tonsillectomy and had a diagnosis of asthma. Before the surgery, each caregiver filled out a questionnaire asking about medication use, asthma severity, and school and work days missed because of asthma exacerbation. Caregivers were contacted a mean of 1 year later and asked the same questions.

Medication use dropped significantly after surgery. The number of patients using inhaled steroids decreased from 25 to 14, albuterol from 30 to 18, and leukotriene moderators from 16 to 11. The single patient who was taking a long-acting β₂-agonist before surgery was no longer taking it afterward.

The use of systemic steroids decreased as well. Before surgery, 22 patients used the drugs at least once a year; 8 required one course, 5 required two courses, 3 required three courses, and 6 required four courses. After surgery, only eight patients were using systemic steroids; all required one or two courses.

Caregivers also reported an average decrease from 2.0 to 0.81 in asthma severity symptom scores. All classes of asthma severity decreased: The number of children with severe persistent asthma declined from 4 to 0, with moderate persistent from 6 to 2, with mild persistent from 7 to 3, and with mild intermittent from 14 to 13. At the 1-year follow-up, 13 caregivers reported that their child had no asthma symptoms at all.

Of those children who attended school, the average number of missed school days per year decreased from 12.5 to 6. Caregivers' missed work days decreased as well, from 13 to 2 per year.

The relationship between upper airway infection and lower airway dysfunction may explain why some children with asthma experience exacerbations during winter and fall, when upper respiratory infections are more common, and why their symptoms improve with both oral corticosteroids and antibiotics, Dr. Karas said. “There's nothing that shrinks the tonsils like steroids—it's like you're giving a temporary medical tonsillectomy. And antibiotics treat the infective component by preventing those infected secretions that might be micro-aspirated and start up a reactive airway process.”

'We're not saying get a tonsillectomy if you have asthma.' But it's clear that it improves congestion. DR. KARAS

LAS VEGAS – A successful post-hospital discharge headache plan requires three strong pillars: good headache health, good physical health, and good psychological health, Dr. Todd D. Rozen said at a symposium sponsored by the American Headache Society.

A weakness in any of those areas–uncontrolled headache, uncontrolled diabetes or hypertension, or unaddressed psychological problems–can ignite a cycle of pain and analgesic use that may result in a medication overuse headache and land the patient in the hospital again, Dr. Rozen said.

Discharge planning is probably the most important factor in preventing headache disability and rebound relapse, said Dr. Rozen of the Michigan Head-Pain and Neurological Institute, Ann Arbor. “The hard part is not what happens in the hospital. It's what happens after they leave. That's where all the work takes place.”

The first step is to establish an effective abortive plan to keep headache pain under control, he said. That means picking and choosing which pain to treat. “The hardest step is learning that we don't treat mild pain anymore. If you've been an analgesic overuser, you have to retrain the brain to understand that it's not going to get medication every time it wants it.”

The patient should not be a martyr, however. “Sometimes they go the opposite way and don't take their medication enough. Make sure they aren't underusing it, because allowing the pain to progress may actually make it worse,” Dr. Rozen said.

Hydration, moderate exercise (20 minutes per day, two or three times per week), and relaxation techniques will help the patient cope with mild pain. For moderate pain, NSAIDs may be used, but no more than four times per week. If the pain is not accompanied by nausea, then the patient should take the NSAID alone. If nausea is present or if the pain is escalating, then the patient can add a dopamine antagonist, but no more than twice a week; these drugs are helpful in treating pain and also speed up NSAID absorption.

For severe pain, most patents probably will not be taking triptans, since they were most likely overusing those drugs. Dihydroergotamine is one option; it has a much longer half-life than a triptan and poses less of a rebound risk.

Every discharge plan should include rescue therapy. “There are always going to be times when none of these medications work,” Dr. Rozen said. Indomethacin suppositories or atypical antipsychotics can be of use, as can high-dose, as-needed antiepileptics. Those that increase γ-aminobutyric acid (GABA) are probably most useful, since they work on the pain and are nonaddicting. Consider pregabalin, gabapentin, topiramate, or levetiracetam. Opiates are almost never used in this population.

An effective preventive-therapy program is essential. Most patients will do well on oral forms of whatever intravenous therapy they responded to while in the hospital: magnesium, a dopamine receptor antagonist, valproate, dihydroergotamine, corticosteroids, or antihistamine.

No discharge plan will be effective, however, if underlying psychological and physical problems aren't addressed. This requires appropriate referral, Dr. Rozen said. “Don't try to be the primary care provider for psychiatric conditions. You don't have that expertise.”

The importance of addressing these problems cannot be overemphasized. Studies show that only 20% of headache patients with depression will improve, compared with 70% of those without depression. Uncontrolled diabetes, hypertension, and thyroid problems can have a significant impact on headache pain as well.

Follow-up is important with these patients, Dr. Rozen stressed. They should be seen every 4 weeks until you are sure they are doing well. “This is your opportunity to monitor their progress and cheer them on,” as well as to adjust medication dosages and help set realistic goals.

“They need to understand that getting headache under control will take time,” he noted. “By month 1, we shoot for 1 hour of headache-free time. By month 2, we look for a 20%–30% improvement, and by month 3, a 50% improvement. They can't expect to get better in just 2 or 3 weeks.”

LAS VEGAS – A successful post-hospital discharge headache plan requires three strong pillars: good headache health, good physical health, and good psychological health, Dr. Todd D. Rozen said at a symposium sponsored by the American Headache Society.

A weakness in any of those areas–uncontrolled headache, uncontrolled diabetes or hypertension, or unaddressed psychological problems–can ignite a cycle of pain and analgesic use that may result in a medication overuse headache and land the patient in the hospital again, Dr. Rozen said.

Discharge planning is probably the most important factor in preventing headache disability and rebound relapse, said Dr. Rozen of the Michigan Head-Pain and Neurological Institute, Ann Arbor. “The hard part is not what happens in the hospital. It's what happens after they leave. That's where all the work takes place.”

The first step is to establish an effective abortive plan to keep headache pain under control, he said. That means picking and choosing which pain to treat. “The hardest step is learning that we don't treat mild pain anymore. If you've been an analgesic overuser, you have to retrain the brain to understand that it's not going to get medication every time it wants it.”

The patient should not be a martyr, however. “Sometimes they go the opposite way and don't take their medication enough. Make sure they aren't underusing it, because allowing the pain to progress may actually make it worse,” Dr. Rozen said.

Hydration, moderate exercise (20 minutes per day, two or three times per week), and relaxation techniques will help the patient cope with mild pain. For moderate pain, NSAIDs may be used, but no more than four times per week. If the pain is not accompanied by nausea, then the patient should take the NSAID alone. If nausea is present or if the pain is escalating, then the patient can add a dopamine antagonist, but no more than twice a week; these drugs are helpful in treating pain and also speed up NSAID absorption.

For severe pain, most patents probably will not be taking triptans, since they were most likely overusing those drugs. Dihydroergotamine is one option; it has a much longer half-life than a triptan and poses less of a rebound risk.

Every discharge plan should include rescue therapy. “There are always going to be times when none of these medications work,” Dr. Rozen said. Indomethacin suppositories or atypical antipsychotics can be of use, as can high-dose, as-needed antiepileptics. Those that increase γ-aminobutyric acid (GABA) are probably most useful, since they work on the pain and are nonaddicting. Consider pregabalin, gabapentin, topiramate, or levetiracetam. Opiates are almost never used in this population.

An effective preventive-therapy program is essential. Most patients will do well on oral forms of whatever intravenous therapy they responded to while in the hospital: magnesium, a dopamine receptor antagonist, valproate, dihydroergotamine, corticosteroids, or antihistamine.

No discharge plan will be effective, however, if underlying psychological and physical problems aren't addressed. This requires appropriate referral, Dr. Rozen said. “Don't try to be the primary care provider for psychiatric conditions. You don't have that expertise.”

The importance of addressing these problems cannot be overemphasized. Studies show that only 20% of headache patients with depression will improve, compared with 70% of those without depression. Uncontrolled diabetes, hypertension, and thyroid problems can have a significant impact on headache pain as well.

Follow-up is important with these patients, Dr. Rozen stressed. They should be seen every 4 weeks until you are sure they are doing well. “This is your opportunity to monitor their progress and cheer them on,” as well as to adjust medication dosages and help set realistic goals.

“They need to understand that getting headache under control will take time,” he noted. “By month 1, we shoot for 1 hour of headache-free time. By month 2, we look for a 20%–30% improvement, and by month 3, a 50% improvement. They can't expect to get better in just 2 or 3 weeks.”

LAS VEGAS – A successful post-hospital discharge headache plan requires three strong pillars: good headache health, good physical health, and good psychological health, Dr. Todd D. Rozen said at a symposium sponsored by the American Headache Society.

A weakness in any of those areas–uncontrolled headache, uncontrolled diabetes or hypertension, or unaddressed psychological problems–can ignite a cycle of pain and analgesic use that may result in a medication overuse headache and land the patient in the hospital again, Dr. Rozen said.

Discharge planning is probably the most important factor in preventing headache disability and rebound relapse, said Dr. Rozen of the Michigan Head-Pain and Neurological Institute, Ann Arbor. “The hard part is not what happens in the hospital. It's what happens after they leave. That's where all the work takes place.”

The first step is to establish an effective abortive plan to keep headache pain under control, he said. That means picking and choosing which pain to treat. “The hardest step is learning that we don't treat mild pain anymore. If you've been an analgesic overuser, you have to retrain the brain to understand that it's not going to get medication every time it wants it.”

The patient should not be a martyr, however. “Sometimes they go the opposite way and don't take their medication enough. Make sure they aren't underusing it, because allowing the pain to progress may actually make it worse,” Dr. Rozen said.

Hydration, moderate exercise (20 minutes per day, two or three times per week), and relaxation techniques will help the patient cope with mild pain. For moderate pain, NSAIDs may be used, but no more than four times per week. If the pain is not accompanied by nausea, then the patient should take the NSAID alone. If nausea is present or if the pain is escalating, then the patient can add a dopamine antagonist, but no more than twice a week; these drugs are helpful in treating pain and also speed up NSAID absorption.

For severe pain, most patents probably will not be taking triptans, since they were most likely overusing those drugs. Dihydroergotamine is one option; it has a much longer half-life than a triptan and poses less of a rebound risk.

Every discharge plan should include rescue therapy. “There are always going to be times when none of these medications work,” Dr. Rozen said. Indomethacin suppositories or atypical antipsychotics can be of use, as can high-dose, as-needed antiepileptics. Those that increase γ-aminobutyric acid (GABA) are probably most useful, since they work on the pain and are nonaddicting. Consider pregabalin, gabapentin, topiramate, or levetiracetam. Opiates are almost never used in this population.

An effective preventive-therapy program is essential. Most patients will do well on oral forms of whatever intravenous therapy they responded to while in the hospital: magnesium, a dopamine receptor antagonist, valproate, dihydroergotamine, corticosteroids, or antihistamine.

No discharge plan will be effective, however, if underlying psychological and physical problems aren't addressed. This requires appropriate referral, Dr. Rozen said. “Don't try to be the primary care provider for psychiatric conditions. You don't have that expertise.”

The importance of addressing these problems cannot be overemphasized. Studies show that only 20% of headache patients with depression will improve, compared with 70% of those without depression. Uncontrolled diabetes, hypertension, and thyroid problems can have a significant impact on headache pain as well.

Follow-up is important with these patients, Dr. Rozen stressed. They should be seen every 4 weeks until you are sure they are doing well. “This is your opportunity to monitor their progress and cheer them on,” as well as to adjust medication dosages and help set realistic goals.

“They need to understand that getting headache under control will take time,” he noted. “By month 1, we shoot for 1 hour of headache-free time. By month 2, we look for a 20%–30% improvement, and by month 3, a 50% improvement. They can't expect to get better in just 2 or 3 weeks.”

Amnestic mild cognitive impairment is neuropathologically the same entity as early Alzheimer's disease and represents a transition from the normal aging brain to the profound pathology of Alzheimer's, according to Dr. William Markesberry and colleagues.

The transition appears to be marked more by an increase in neurofibrillatory tangles than in dendritic or neuritic plaques, wrote Dr. Markesberry of the University of Kentucky, Lexington, and his associates.

The researchers followed 43 elderly subjects who were cognitively normal at baseline, until their deaths: 23 of them remained cognitively normal, 10 developed amnestic MCI, and 10 developed early Alzheimer's disease (EAD).

All of the brains were available for autopsy via prior arrangement with the subjects (Arch. Neurol. 2006;63:38–46).

Comparison of the brains from patients with EAD to normal brains found significant increases in all the pathologic hallmarks of the disease (dendritic plaques, neuritic plaques, and neurofibrillatory tangles) in all of the neocortical and ventromedial regions.

There were no significant differences in the number of dendritic plaques between the controls and those with MCI, nor between the MCI brains and the EAD brains. “Because dendritic plaques were so common in normal control subjects, our data suggest that they are not critical neuropathologic determinants of the transition from normal to MCI, or MCI to EAD,” the investigators wrote.

Neuritic plaques were significantly more common in the MCI brains than in the control brains. But when the MCI brains were compared with EAD brains, the plaques only increased significantly in the amygdala and subiculum.

“This indicates that the pathologic deposition of insoluble β-amyloid peptide and formation of neurites in the cerebral cortex progress from normal to MCI, but in contrast, they do not distinguish MCI from EAD.”

The most striking difference between the brains was the amount of neurofibrillatory tangling. Compared with normal brains, the MCI brains showed significantly more tangles in the inferior parietal lobule, amygdala, entorhinal cortex, and subiculum. When compared with MCI brains, EAD brains showed an expansion of the tangles, with significantly more in the middle temporal gyrus, middle temporal gyrus, amygdala, and subiculum.

These changes imply neuropathologic progression, the researchers wrote. “The increase in [tangles] in all of the neocortical and ventromedial lobe structures in EAD, compared with controls, further supports a gradual increase in [tangle] formation from normal aging to having MCI to having EAD.”

The conclusions argue for a change in the diagnostic criteria of early Alzheimer's and MCI, Dr. John Morris wrote in an accompanying editorial.

The standard criteria, which were developed years ago, can't distinguish between the mild stages of Alzheimer's and MCI that are now identifiable, wrote Dr. Morris of Washington University, St. Louis (Arch. Neurol. 2006;63:15–6).

“Revised criteria should permit the diagnosis of AD at these early stages, because … AD pathology is already established. Moreover, the earliest stages of AD may be the optimal time for interventions with drugs now in development that have the potential to retard or even arrest the AD process.”

Amnestic mild cognitive impairment is neuropathologically the same entity as early Alzheimer's disease and represents a transition from the normal aging brain to the profound pathology of Alzheimer's, according to Dr. William Markesberry and colleagues.

The transition appears to be marked more by an increase in neurofibrillatory tangles than in dendritic or neuritic plaques, wrote Dr. Markesberry of the University of Kentucky, Lexington, and his associates.

The researchers followed 43 elderly subjects who were cognitively normal at baseline, until their deaths: 23 of them remained cognitively normal, 10 developed amnestic MCI, and 10 developed early Alzheimer's disease (EAD).

All of the brains were available for autopsy via prior arrangement with the subjects (Arch. Neurol. 2006;63:38–46).

Comparison of the brains from patients with EAD to normal brains found significant increases in all the pathologic hallmarks of the disease (dendritic plaques, neuritic plaques, and neurofibrillatory tangles) in all of the neocortical and ventromedial regions.

There were no significant differences in the number of dendritic plaques between the controls and those with MCI, nor between the MCI brains and the EAD brains. “Because dendritic plaques were so common in normal control subjects, our data suggest that they are not critical neuropathologic determinants of the transition from normal to MCI, or MCI to EAD,” the investigators wrote.

Neuritic plaques were significantly more common in the MCI brains than in the control brains. But when the MCI brains were compared with EAD brains, the plaques only increased significantly in the amygdala and subiculum.

“This indicates that the pathologic deposition of insoluble β-amyloid peptide and formation of neurites in the cerebral cortex progress from normal to MCI, but in contrast, they do not distinguish MCI from EAD.”

The most striking difference between the brains was the amount of neurofibrillatory tangling. Compared with normal brains, the MCI brains showed significantly more tangles in the inferior parietal lobule, amygdala, entorhinal cortex, and subiculum. When compared with MCI brains, EAD brains showed an expansion of the tangles, with significantly more in the middle temporal gyrus, middle temporal gyrus, amygdala, and subiculum.

These changes imply neuropathologic progression, the researchers wrote. “The increase in [tangles] in all of the neocortical and ventromedial lobe structures in EAD, compared with controls, further supports a gradual increase in [tangle] formation from normal aging to having MCI to having EAD.”

The conclusions argue for a change in the diagnostic criteria of early Alzheimer's and MCI, Dr. John Morris wrote in an accompanying editorial.

The standard criteria, which were developed years ago, can't distinguish between the mild stages of Alzheimer's and MCI that are now identifiable, wrote Dr. Morris of Washington University, St. Louis (Arch. Neurol. 2006;63:15–6).

“Revised criteria should permit the diagnosis of AD at these early stages, because … AD pathology is already established. Moreover, the earliest stages of AD may be the optimal time for interventions with drugs now in development that have the potential to retard or even arrest the AD process.”

Amnestic mild cognitive impairment is neuropathologically the same entity as early Alzheimer's disease and represents a transition from the normal aging brain to the profound pathology of Alzheimer's, according to Dr. William Markesberry and colleagues.

The transition appears to be marked more by an increase in neurofibrillatory tangles than in dendritic or neuritic plaques, wrote Dr. Markesberry of the University of Kentucky, Lexington, and his associates.

The researchers followed 43 elderly subjects who were cognitively normal at baseline, until their deaths: 23 of them remained cognitively normal, 10 developed amnestic MCI, and 10 developed early Alzheimer's disease (EAD).

All of the brains were available for autopsy via prior arrangement with the subjects (Arch. Neurol. 2006;63:38–46).

Comparison of the brains from patients with EAD to normal brains found significant increases in all the pathologic hallmarks of the disease (dendritic plaques, neuritic plaques, and neurofibrillatory tangles) in all of the neocortical and ventromedial regions.

There were no significant differences in the number of dendritic plaques between the controls and those with MCI, nor between the MCI brains and the EAD brains. “Because dendritic plaques were so common in normal control subjects, our data suggest that they are not critical neuropathologic determinants of the transition from normal to MCI, or MCI to EAD,” the investigators wrote.

Neuritic plaques were significantly more common in the MCI brains than in the control brains. But when the MCI brains were compared with EAD brains, the plaques only increased significantly in the amygdala and subiculum.

“This indicates that the pathologic deposition of insoluble β-amyloid peptide and formation of neurites in the cerebral cortex progress from normal to MCI, but in contrast, they do not distinguish MCI from EAD.”

The most striking difference between the brains was the amount of neurofibrillatory tangling. Compared with normal brains, the MCI brains showed significantly more tangles in the inferior parietal lobule, amygdala, entorhinal cortex, and subiculum. When compared with MCI brains, EAD brains showed an expansion of the tangles, with significantly more in the middle temporal gyrus, middle temporal gyrus, amygdala, and subiculum.

These changes imply neuropathologic progression, the researchers wrote. “The increase in [tangles] in all of the neocortical and ventromedial lobe structures in EAD, compared with controls, further supports a gradual increase in [tangle] formation from normal aging to having MCI to having EAD.”

The conclusions argue for a change in the diagnostic criteria of early Alzheimer's and MCI, Dr. John Morris wrote in an accompanying editorial.

The standard criteria, which were developed years ago, can't distinguish between the mild stages of Alzheimer's and MCI that are now identifiable, wrote Dr. Morris of Washington University, St. Louis (Arch. Neurol. 2006;63:15–6).

“Revised criteria should permit the diagnosis of AD at these early stages, because … AD pathology is already established. Moreover, the earliest stages of AD may be the optimal time for interventions with drugs now in development that have the potential to retard or even arrest the AD process.”