Parkinson's Disease

Playing table tennis, also known as ping-pong, appears to improve motor symptoms in patients with Parkinson’s disease, new research suggests. The results of a small pilot study show that table ping-pong is a safe and effective rehabilitative intervention for patients with Parkinson’s disease that can be easily introduced, study investigator Shinsuke Fujioka, MD, Department of Neurology, Fukuoka University, Japan, told Medscape Medical News.

He emphasized that any rehabilitation for patients with Parkinson’s disease could be beneficial, especially during the early stages of their illness. “The most important thing is that patients have fun when doing rehabilitation.”

The findings were released February 25 ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology. The AAN canceled the meeting and released abstracts and access to presenters for press coverage.
 

All exercise beneficial

The idea of studying ping-pong as a therapy for patients with Parkinson’s disease originated when Dr. Fujioka heard about a patient who used a cane but no longer needed it after taking up the exercise as a weekly rehabilitation therapy.

“It’s apparent that the exercise can improve motor function of Parkinson’s disease. However, to date, the effects of the sport have not been well investigated for this patient population, so our study aimed to disclose the effects that table tennis can bring to patients with Parkinson’s disease,” said Dr. Fujioka.

The study included 12 patients with Parkinson’s disease – 10 women and two men. Mean age at disease onset was 67 years, and mean disease duration was 7 years. Mean stage on the Hoehn & Yahr scale, which assesses severity of Parkinson’s disease symptoms, was three, so most patients had balance problems.

Study participants played ping-pong at once-weekly 5-hour sessions that included rest breaks whenever they felt it was necessary.

Researchers assessed participants using the Unified Parkinson’s Disease Rating Scale (UPDRS) part I-IV. Parts II and III assess motor function whereas parts I and IV evaluate nonmotor function and motor complications, respectively.

The main motor symptoms of Parkinson’s disease include bradykinesia and muscle rigidity, tremor, and postural instability.

Researchers also assessed participants using the Montreal Cognitive Assessment (MoCA), Frontal Assessment Battery (FAB), Self-Rating Depression Scale (SDS), and Apathy scale.

Results showed that UPDRS part II significantly improved at 3 and 6 months (both P < 0.001), as did UPDRS part III (P = 0.002 at 3 months; P < 0.001 at 6 months).

Dr. Fujioka speculated, “twisting axial muscles when hitting a ping-pong ball may be the most efficacious for patients, especially for bradykinesia and balance problems.”
 

Significant improvement

Such findings may not be that surprising. Dr. Fujioka pointed to other rehabilitation therapies such as tai chi or tango that may also improve Parkinson’s disease motor symptoms.

For UPDRS part II, subscores of speech, saliva and drooling, dressing, handwriting, doing hobbies and other activities, getting out of bed, a car, or a deep chair, and walking and balance, significantly improved.

In addition, for UPDRS part III, subscores of facial expression, rigidity, postural stability, posture, bradykinesia, and kinetic tremor of the hands also significantly improved.

As for nonmotor symptoms such as mood, anxiety, depression, and apathy assessed in UPDRS part I, scores did not significantly change, which was also the case for part IV.

However, Dr. Fujioka pointed out that patient scores didn’t worsen. “Given the nature of disease, not worsening of nonmotor features can potentially be a good effect of the sport.” MoCA, FAB, SDS, and Apathy scale scores also did not change.

Dr. Fujioka noted that all participants enjoyed the table tennis rehabilitation, and “gradually smiled more during the study period.” All study participants continued the table tennis rehabilitation after the 6-month program.

Dr. Fujioka noted that although patients with Parkinson’s disease often have difficulty moving in a front-to-back direction, they can move relatively easily in a lateral direction.

“In that sense, table tennis is suitable for them,” he said. However, he added, court tennis, handball, and badminton may not be suitable for most patients with Parkinson’s disease.

One patient suffered a fall and another backache. Dr. Fujioka cautioned that more frequent ping-pong playing might increase the risk of adverse events.

He also suggests patients with Parkinson’s disease have their bone density checked before starting regular rehabilitation exercise as they are at increased risk for osteoporosis.

The investigators are currently organizing a prospective, multicenter randomized study to compare the effectiveness of table tennis with conventional rehabilitation and the Lee Silverman Voice Treatment, which is designed to increase vocal intensity in patients with Parkinson’s disease.
 

Fun, engaging

Commenting on the findings, Cynthia Comella, MD, professor emeritus, Neurological Sciences, Rush University Medical Center, New Philadelphia, Ohio, said ping-pong is a “fun and engaging” exercise for patients with Parkinson’s disease. Dr. Comella noted prior studies have shown many types of exercise are beneficial for patients with Parkinson’s disease “provided that they continue” with it.

In that regard, these new results are “promising,” she said. “It may be that this type of community generating, fun exercise would lead to a continuation of the exercise after a study is completed.”

A controlled trial that includes a post-study follow-up to evaluate compliance and continued benefit is needed, she said.

Purchase of equipment, including tables, rackets, and balls, was possible through funds donated by Hisako Kobayashi-Levin, which provides Murakami Karindoh Hospital with an annual fund to improve the quality of their rehabilitation program. The authors reported no relevant financial relationships.

This article first appeared on Medscape.com.

Playing table tennis, also known as ping-pong, appears to improve motor symptoms in patients with Parkinson’s disease, new research suggests. The results of a small pilot study show that table ping-pong is a safe and effective rehabilitative intervention for patients with Parkinson’s disease that can be easily introduced, study investigator Shinsuke Fujioka, MD, Department of Neurology, Fukuoka University, Japan, told Medscape Medical News.

He emphasized that any rehabilitation for patients with Parkinson’s disease could be beneficial, especially during the early stages of their illness. “The most important thing is that patients have fun when doing rehabilitation.”

The findings were released February 25 ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology. The AAN canceled the meeting and released abstracts and access to presenters for press coverage.
 

All exercise beneficial

The idea of studying ping-pong as a therapy for patients with Parkinson’s disease originated when Dr. Fujioka heard about a patient who used a cane but no longer needed it after taking up the exercise as a weekly rehabilitation therapy.

“It’s apparent that the exercise can improve motor function of Parkinson’s disease. However, to date, the effects of the sport have not been well investigated for this patient population, so our study aimed to disclose the effects that table tennis can bring to patients with Parkinson’s disease,” said Dr. Fujioka.

The study included 12 patients with Parkinson’s disease – 10 women and two men. Mean age at disease onset was 67 years, and mean disease duration was 7 years. Mean stage on the Hoehn & Yahr scale, which assesses severity of Parkinson’s disease symptoms, was three, so most patients had balance problems.

Study participants played ping-pong at once-weekly 5-hour sessions that included rest breaks whenever they felt it was necessary.

Researchers assessed participants using the Unified Parkinson’s Disease Rating Scale (UPDRS) part I-IV. Parts II and III assess motor function whereas parts I and IV evaluate nonmotor function and motor complications, respectively.

The main motor symptoms of Parkinson’s disease include bradykinesia and muscle rigidity, tremor, and postural instability.

Researchers also assessed participants using the Montreal Cognitive Assessment (MoCA), Frontal Assessment Battery (FAB), Self-Rating Depression Scale (SDS), and Apathy scale.

Results showed that UPDRS part II significantly improved at 3 and 6 months (both P < 0.001), as did UPDRS part III (P = 0.002 at 3 months; P < 0.001 at 6 months).

Dr. Fujioka speculated, “twisting axial muscles when hitting a ping-pong ball may be the most efficacious for patients, especially for bradykinesia and balance problems.”
 

Significant improvement

Such findings may not be that surprising. Dr. Fujioka pointed to other rehabilitation therapies such as tai chi or tango that may also improve Parkinson’s disease motor symptoms.

For UPDRS part II, subscores of speech, saliva and drooling, dressing, handwriting, doing hobbies and other activities, getting out of bed, a car, or a deep chair, and walking and balance, significantly improved.

In addition, for UPDRS part III, subscores of facial expression, rigidity, postural stability, posture, bradykinesia, and kinetic tremor of the hands also significantly improved.

As for nonmotor symptoms such as mood, anxiety, depression, and apathy assessed in UPDRS part I, scores did not significantly change, which was also the case for part IV.

However, Dr. Fujioka pointed out that patient scores didn’t worsen. “Given the nature of disease, not worsening of nonmotor features can potentially be a good effect of the sport.” MoCA, FAB, SDS, and Apathy scale scores also did not change.

Dr. Fujioka noted that all participants enjoyed the table tennis rehabilitation, and “gradually smiled more during the study period.” All study participants continued the table tennis rehabilitation after the 6-month program.

Dr. Fujioka noted that although patients with Parkinson’s disease often have difficulty moving in a front-to-back direction, they can move relatively easily in a lateral direction.

“In that sense, table tennis is suitable for them,” he said. However, he added, court tennis, handball, and badminton may not be suitable for most patients with Parkinson’s disease.

One patient suffered a fall and another backache. Dr. Fujioka cautioned that more frequent ping-pong playing might increase the risk of adverse events.

He also suggests patients with Parkinson’s disease have their bone density checked before starting regular rehabilitation exercise as they are at increased risk for osteoporosis.

The investigators are currently organizing a prospective, multicenter randomized study to compare the effectiveness of table tennis with conventional rehabilitation and the Lee Silverman Voice Treatment, which is designed to increase vocal intensity in patients with Parkinson’s disease.
 

Fun, engaging

Commenting on the findings, Cynthia Comella, MD, professor emeritus, Neurological Sciences, Rush University Medical Center, New Philadelphia, Ohio, said ping-pong is a “fun and engaging” exercise for patients with Parkinson’s disease. Dr. Comella noted prior studies have shown many types of exercise are beneficial for patients with Parkinson’s disease “provided that they continue” with it.

In that regard, these new results are “promising,” she said. “It may be that this type of community generating, fun exercise would lead to a continuation of the exercise after a study is completed.”

A controlled trial that includes a post-study follow-up to evaluate compliance and continued benefit is needed, she said.

Purchase of equipment, including tables, rackets, and balls, was possible through funds donated by Hisako Kobayashi-Levin, which provides Murakami Karindoh Hospital with an annual fund to improve the quality of their rehabilitation program. The authors reported no relevant financial relationships.

This article first appeared on Medscape.com.

Playing table tennis, also known as ping-pong, appears to improve motor symptoms in patients with Parkinson’s disease, new research suggests. The results of a small pilot study show that table ping-pong is a safe and effective rehabilitative intervention for patients with Parkinson’s disease that can be easily introduced, study investigator Shinsuke Fujioka, MD, Department of Neurology, Fukuoka University, Japan, told Medscape Medical News.

He emphasized that any rehabilitation for patients with Parkinson’s disease could be beneficial, especially during the early stages of their illness. “The most important thing is that patients have fun when doing rehabilitation.”

The findings were released February 25 ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology. The AAN canceled the meeting and released abstracts and access to presenters for press coverage.
 

All exercise beneficial

The idea of studying ping-pong as a therapy for patients with Parkinson’s disease originated when Dr. Fujioka heard about a patient who used a cane but no longer needed it after taking up the exercise as a weekly rehabilitation therapy.

“It’s apparent that the exercise can improve motor function of Parkinson’s disease. However, to date, the effects of the sport have not been well investigated for this patient population, so our study aimed to disclose the effects that table tennis can bring to patients with Parkinson’s disease,” said Dr. Fujioka.

The study included 12 patients with Parkinson’s disease – 10 women and two men. Mean age at disease onset was 67 years, and mean disease duration was 7 years. Mean stage on the Hoehn & Yahr scale, which assesses severity of Parkinson’s disease symptoms, was three, so most patients had balance problems.

Study participants played ping-pong at once-weekly 5-hour sessions that included rest breaks whenever they felt it was necessary.

Researchers assessed participants using the Unified Parkinson’s Disease Rating Scale (UPDRS) part I-IV. Parts II and III assess motor function whereas parts I and IV evaluate nonmotor function and motor complications, respectively.

The main motor symptoms of Parkinson’s disease include bradykinesia and muscle rigidity, tremor, and postural instability.

Researchers also assessed participants using the Montreal Cognitive Assessment (MoCA), Frontal Assessment Battery (FAB), Self-Rating Depression Scale (SDS), and Apathy scale.

Results showed that UPDRS part II significantly improved at 3 and 6 months (both P < 0.001), as did UPDRS part III (P = 0.002 at 3 months; P < 0.001 at 6 months).

Dr. Fujioka speculated, “twisting axial muscles when hitting a ping-pong ball may be the most efficacious for patients, especially for bradykinesia and balance problems.”
 

Significant improvement

Such findings may not be that surprising. Dr. Fujioka pointed to other rehabilitation therapies such as tai chi or tango that may also improve Parkinson’s disease motor symptoms.

For UPDRS part II, subscores of speech, saliva and drooling, dressing, handwriting, doing hobbies and other activities, getting out of bed, a car, or a deep chair, and walking and balance, significantly improved.

In addition, for UPDRS part III, subscores of facial expression, rigidity, postural stability, posture, bradykinesia, and kinetic tremor of the hands also significantly improved.

As for nonmotor symptoms such as mood, anxiety, depression, and apathy assessed in UPDRS part I, scores did not significantly change, which was also the case for part IV.

However, Dr. Fujioka pointed out that patient scores didn’t worsen. “Given the nature of disease, not worsening of nonmotor features can potentially be a good effect of the sport.” MoCA, FAB, SDS, and Apathy scale scores also did not change.

Dr. Fujioka noted that all participants enjoyed the table tennis rehabilitation, and “gradually smiled more during the study period.” All study participants continued the table tennis rehabilitation after the 6-month program.

Dr. Fujioka noted that although patients with Parkinson’s disease often have difficulty moving in a front-to-back direction, they can move relatively easily in a lateral direction.

“In that sense, table tennis is suitable for them,” he said. However, he added, court tennis, handball, and badminton may not be suitable for most patients with Parkinson’s disease.

One patient suffered a fall and another backache. Dr. Fujioka cautioned that more frequent ping-pong playing might increase the risk of adverse events.

He also suggests patients with Parkinson’s disease have their bone density checked before starting regular rehabilitation exercise as they are at increased risk for osteoporosis.

The investigators are currently organizing a prospective, multicenter randomized study to compare the effectiveness of table tennis with conventional rehabilitation and the Lee Silverman Voice Treatment, which is designed to increase vocal intensity in patients with Parkinson’s disease.
 

Fun, engaging

Commenting on the findings, Cynthia Comella, MD, professor emeritus, Neurological Sciences, Rush University Medical Center, New Philadelphia, Ohio, said ping-pong is a “fun and engaging” exercise for patients with Parkinson’s disease. Dr. Comella noted prior studies have shown many types of exercise are beneficial for patients with Parkinson’s disease “provided that they continue” with it.

In that regard, these new results are “promising,” she said. “It may be that this type of community generating, fun exercise would lead to a continuation of the exercise after a study is completed.”

A controlled trial that includes a post-study follow-up to evaluate compliance and continued benefit is needed, she said.

Purchase of equipment, including tables, rackets, and balls, was possible through funds donated by Hisako Kobayashi-Levin, which provides Murakami Karindoh Hospital with an annual fund to improve the quality of their rehabilitation program. The authors reported no relevant financial relationships.

This article first appeared on Medscape.com.

Telephone-based cognitive behavioral therapy (CBT) significantly improves depression, anxiety, and quality of life in patients with Parkinson’s disease, relative to usual care, according to trial results published in Neurology. The treatment’s effect on depression is “moderated by the reduction of negative thoughts,” the target of the intervention, the researchers said.

Telephone-based CBT may be a convenient option for patients, said lead study author Roseanne D. Dobkin, PhD, of the department of psychiatry at Rutgers Robert Wood Johnson Medical School in Piscataway, N.J., and the VA New Jersey Health Care System in Lyons. “A notable proportion of people with Parkinson’s [disease] do not receive the much needed mental health treatment to facilitate proactive coping with the daily challenges superimposed by their medical condition,” Dr. Dobkin said in a news release. “This study suggests that the effects of the [CBT] last long beyond when the treatment stopped and can be used alongside standard neurological care.”

An undertreated problem

Although depression affects about half of patients with Parkinson’s disease and is associated with physical and cognitive decline, it often goes overlooked and undertreated, the study authors said. Data about the efficacy and tolerability of antidepressants are mixed. CBT holds promise for reducing depression in Parkinson’s disease, prior research suggests, but patients may have limited access to in-person sessions because of physical and geographic barriers.

To assess the efficacy of telephone-based CBT for depression in Parkinson’s disease, compared with community-based treatment as usual, Dr. Dobkin and colleagues conducted a randomized controlled trial. Their study included 72 patients with Parkinson’s disease at an academic medical center. Participants had a depressive disorder, were between aged 35 and 85 years, had stable Parkinson’s disease and mental health treatment for at least 6 weeks, and had a family member or friend willing to participate in the study. The investigators excluded patients with possible dementia or marked cognitive impairment and active suicidal plans or intent.

Participants were randomly assigned to receive usual care plus telephone-based CBT or usual care only. Patients taking antidepressants were evenly divided between the groups.

Telephone-based CBT consisted of weekly 1-hour sessions for 10 weeks. During 6 months of follow-up, patients could receive one session per month if desired. The CBT “targeted negative thoughts (e.g., ‘I have no control’; ‘I am helpless’) and behaviors (e.g., avoidance, excessive worry, lack of exercise),” the investigators said. In addition, therapists trained patients’ care partners by telephone to help patients between sessions. Treatment as usual was defined by patients’ health care teams. For most participants in both groups, treatment as usual included taking antidepressant medication or receiving psychotherapy in the community.

Change in Hamilton Depression Rating Scale (HAM-D) score was the primary outcome. Secondary outcomes included whether patients considered their depression much improved and improvements in depression severity (as measured by the Beck Depression Inventory [BDI]), anxiety (as measured by the Hamilton Anxiety Rating Scale [HAM-A]), and quality of life. The researchers also assessed negative thinking using the Inference Questionnaire. Blinded raters assessed outcomes.
 

Sustained improvements

Thirty-seven patients were randomized to receive telephone-based CBT, and 35 were randomized to treatment as usual. Overall, 70% were taking antidepressants, and 14% continued receiving psychotherapy from community providers of their choice during the trial. Participants’ average age was 65 years, and 51% were female.

Post treatment, mean improvement in HAM-D score from baseline was 6.53 points in the telephone-based CBT group, compared with −0.27 points in the control group. “Effects at the end of treatment were maintained at 6-month follow-up,” the researchers reported.

About 40% of patients in the CBT group reported that their depression was much improved or very much improved, compared with none of the patients in the control group. Responders had mild to minimal symptomatology on the HAM-D, which indicates that the changes were clinically significant, the authors said.

Secondary outcomes also favored telephone-based CBT. “The intervention was feasible and highly acceptable, yielding an 88% retention rate over the 9-month trial,” Dr. Dobkin and colleagues said.

Compared with other control conditions, treatment-as-usual controls may enhance the effect size of an intervention, the authors noted. In addition, factors such as therapeutic relationship, time, and attention likely contribute to psychotherapy outcomes.
 

Success may hinge on cognitive ability

“The success of this trial highlights the need for further efficacy studies targeting neuropsychiatric manifestations of [Parkinson’s disease] and adds urgency to the discussion over policies regarding access to tele–mental health, especially for vulnerable populations with limited access to in-person mental health services,” Gregory M. Pontone, MD, and Kelly A. Mills, MD, wrote in an accompanying editorial. Dr. Pontone and Dr. Mills are affiliated with Johns Hopkins University in Baltimore.

“Only rudimentary evidence” exists to guide the treatment of depression in patients with Parkinson’s disease, the editorialists said. “Patient preference and tolerability suggest that nonpharmacologic therapies, such as CBT, are preferred as first-line treatment. Yet access to qualified CBT practitioners, especially those with a clinical knowledge of [Parkinson’s disease], is limited.”

Despite its advantages and the encouraging results, CBT may have important limitations as well, they said. Patients require a certain degree of cognitive ability to benefit from CBT, and the prevalence of dementia among patients with Parkinson’s disease is about 30%.

Nevertheless, the trial provided evidence of target engagement. “Though caveats include the single-blind design and potential confounding by time spent with patient and caregiver, the authors demonstrated that improvement was mediated by the mechanism of CBT – a reduction in negative thinking.”

The trial was funded by the Michael J. Fox Foundation for Parkinson’s Research and the Parkinson’s Alliance (Parkinson’s Unity Walk). Dr. Mills disclosed a patent pending for a system for phase-dependent cortical brain stimulation, National Institutes of Health funding, pending funding from the Michael J. Fox Foundation, and commercial research support from Global Kinetics Corporation. Dr. Pontone is a consultant for Acadia Pharmaceuticals.

jremaly@mdedge.com

SOURCE: Dobkin RD et al. Neurology. 2020 Apr 1. doi: 10.1212/WNL.0000000000009292.

Telephone-based cognitive behavioral therapy (CBT) significantly improves depression, anxiety, and quality of life in patients with Parkinson’s disease, relative to usual care, according to trial results published in Neurology. The treatment’s effect on depression is “moderated by the reduction of negative thoughts,” the target of the intervention, the researchers said.

Telephone-based CBT may be a convenient option for patients, said lead study author Roseanne D. Dobkin, PhD, of the department of psychiatry at Rutgers Robert Wood Johnson Medical School in Piscataway, N.J., and the VA New Jersey Health Care System in Lyons. “A notable proportion of people with Parkinson’s [disease] do not receive the much needed mental health treatment to facilitate proactive coping with the daily challenges superimposed by their medical condition,” Dr. Dobkin said in a news release. “This study suggests that the effects of the [CBT] last long beyond when the treatment stopped and can be used alongside standard neurological care.”

An undertreated problem

Although depression affects about half of patients with Parkinson’s disease and is associated with physical and cognitive decline, it often goes overlooked and undertreated, the study authors said. Data about the efficacy and tolerability of antidepressants are mixed. CBT holds promise for reducing depression in Parkinson’s disease, prior research suggests, but patients may have limited access to in-person sessions because of physical and geographic barriers.

To assess the efficacy of telephone-based CBT for depression in Parkinson’s disease, compared with community-based treatment as usual, Dr. Dobkin and colleagues conducted a randomized controlled trial. Their study included 72 patients with Parkinson’s disease at an academic medical center. Participants had a depressive disorder, were between aged 35 and 85 years, had stable Parkinson’s disease and mental health treatment for at least 6 weeks, and had a family member or friend willing to participate in the study. The investigators excluded patients with possible dementia or marked cognitive impairment and active suicidal plans or intent.

Participants were randomly assigned to receive usual care plus telephone-based CBT or usual care only. Patients taking antidepressants were evenly divided between the groups.

Telephone-based CBT consisted of weekly 1-hour sessions for 10 weeks. During 6 months of follow-up, patients could receive one session per month if desired. The CBT “targeted negative thoughts (e.g., ‘I have no control’; ‘I am helpless’) and behaviors (e.g., avoidance, excessive worry, lack of exercise),” the investigators said. In addition, therapists trained patients’ care partners by telephone to help patients between sessions. Treatment as usual was defined by patients’ health care teams. For most participants in both groups, treatment as usual included taking antidepressant medication or receiving psychotherapy in the community.

Change in Hamilton Depression Rating Scale (HAM-D) score was the primary outcome. Secondary outcomes included whether patients considered their depression much improved and improvements in depression severity (as measured by the Beck Depression Inventory [BDI]), anxiety (as measured by the Hamilton Anxiety Rating Scale [HAM-A]), and quality of life. The researchers also assessed negative thinking using the Inference Questionnaire. Blinded raters assessed outcomes.
 

Sustained improvements

Thirty-seven patients were randomized to receive telephone-based CBT, and 35 were randomized to treatment as usual. Overall, 70% were taking antidepressants, and 14% continued receiving psychotherapy from community providers of their choice during the trial. Participants’ average age was 65 years, and 51% were female.

Post treatment, mean improvement in HAM-D score from baseline was 6.53 points in the telephone-based CBT group, compared with −0.27 points in the control group. “Effects at the end of treatment were maintained at 6-month follow-up,” the researchers reported.

About 40% of patients in the CBT group reported that their depression was much improved or very much improved, compared with none of the patients in the control group. Responders had mild to minimal symptomatology on the HAM-D, which indicates that the changes were clinically significant, the authors said.

Secondary outcomes also favored telephone-based CBT. “The intervention was feasible and highly acceptable, yielding an 88% retention rate over the 9-month trial,” Dr. Dobkin and colleagues said.

Compared with other control conditions, treatment-as-usual controls may enhance the effect size of an intervention, the authors noted. In addition, factors such as therapeutic relationship, time, and attention likely contribute to psychotherapy outcomes.
 

Success may hinge on cognitive ability

“The success of this trial highlights the need for further efficacy studies targeting neuropsychiatric manifestations of [Parkinson’s disease] and adds urgency to the discussion over policies regarding access to tele–mental health, especially for vulnerable populations with limited access to in-person mental health services,” Gregory M. Pontone, MD, and Kelly A. Mills, MD, wrote in an accompanying editorial. Dr. Pontone and Dr. Mills are affiliated with Johns Hopkins University in Baltimore.

“Only rudimentary evidence” exists to guide the treatment of depression in patients with Parkinson’s disease, the editorialists said. “Patient preference and tolerability suggest that nonpharmacologic therapies, such as CBT, are preferred as first-line treatment. Yet access to qualified CBT practitioners, especially those with a clinical knowledge of [Parkinson’s disease], is limited.”

Despite its advantages and the encouraging results, CBT may have important limitations as well, they said. Patients require a certain degree of cognitive ability to benefit from CBT, and the prevalence of dementia among patients with Parkinson’s disease is about 30%.

Nevertheless, the trial provided evidence of target engagement. “Though caveats include the single-blind design and potential confounding by time spent with patient and caregiver, the authors demonstrated that improvement was mediated by the mechanism of CBT – a reduction in negative thinking.”

The trial was funded by the Michael J. Fox Foundation for Parkinson’s Research and the Parkinson’s Alliance (Parkinson’s Unity Walk). Dr. Mills disclosed a patent pending for a system for phase-dependent cortical brain stimulation, National Institutes of Health funding, pending funding from the Michael J. Fox Foundation, and commercial research support from Global Kinetics Corporation. Dr. Pontone is a consultant for Acadia Pharmaceuticals.

jremaly@mdedge.com

SOURCE: Dobkin RD et al. Neurology. 2020 Apr 1. doi: 10.1212/WNL.0000000000009292.

Telephone-based cognitive behavioral therapy (CBT) significantly improves depression, anxiety, and quality of life in patients with Parkinson’s disease, relative to usual care, according to trial results published in Neurology. The treatment’s effect on depression is “moderated by the reduction of negative thoughts,” the target of the intervention, the researchers said.

Telephone-based CBT may be a convenient option for patients, said lead study author Roseanne D. Dobkin, PhD, of the department of psychiatry at Rutgers Robert Wood Johnson Medical School in Piscataway, N.J., and the VA New Jersey Health Care System in Lyons. “A notable proportion of people with Parkinson’s [disease] do not receive the much needed mental health treatment to facilitate proactive coping with the daily challenges superimposed by their medical condition,” Dr. Dobkin said in a news release. “This study suggests that the effects of the [CBT] last long beyond when the treatment stopped and can be used alongside standard neurological care.”

An undertreated problem

Although depression affects about half of patients with Parkinson’s disease and is associated with physical and cognitive decline, it often goes overlooked and undertreated, the study authors said. Data about the efficacy and tolerability of antidepressants are mixed. CBT holds promise for reducing depression in Parkinson’s disease, prior research suggests, but patients may have limited access to in-person sessions because of physical and geographic barriers.

To assess the efficacy of telephone-based CBT for depression in Parkinson’s disease, compared with community-based treatment as usual, Dr. Dobkin and colleagues conducted a randomized controlled trial. Their study included 72 patients with Parkinson’s disease at an academic medical center. Participants had a depressive disorder, were between aged 35 and 85 years, had stable Parkinson’s disease and mental health treatment for at least 6 weeks, and had a family member or friend willing to participate in the study. The investigators excluded patients with possible dementia or marked cognitive impairment and active suicidal plans or intent.

Participants were randomly assigned to receive usual care plus telephone-based CBT or usual care only. Patients taking antidepressants were evenly divided between the groups.

Telephone-based CBT consisted of weekly 1-hour sessions for 10 weeks. During 6 months of follow-up, patients could receive one session per month if desired. The CBT “targeted negative thoughts (e.g., ‘I have no control’; ‘I am helpless’) and behaviors (e.g., avoidance, excessive worry, lack of exercise),” the investigators said. In addition, therapists trained patients’ care partners by telephone to help patients between sessions. Treatment as usual was defined by patients’ health care teams. For most participants in both groups, treatment as usual included taking antidepressant medication or receiving psychotherapy in the community.

Change in Hamilton Depression Rating Scale (HAM-D) score was the primary outcome. Secondary outcomes included whether patients considered their depression much improved and improvements in depression severity (as measured by the Beck Depression Inventory [BDI]), anxiety (as measured by the Hamilton Anxiety Rating Scale [HAM-A]), and quality of life. The researchers also assessed negative thinking using the Inference Questionnaire. Blinded raters assessed outcomes.
 

Sustained improvements

Thirty-seven patients were randomized to receive telephone-based CBT, and 35 were randomized to treatment as usual. Overall, 70% were taking antidepressants, and 14% continued receiving psychotherapy from community providers of their choice during the trial. Participants’ average age was 65 years, and 51% were female.

Post treatment, mean improvement in HAM-D score from baseline was 6.53 points in the telephone-based CBT group, compared with −0.27 points in the control group. “Effects at the end of treatment were maintained at 6-month follow-up,” the researchers reported.

About 40% of patients in the CBT group reported that their depression was much improved or very much improved, compared with none of the patients in the control group. Responders had mild to minimal symptomatology on the HAM-D, which indicates that the changes were clinically significant, the authors said.

Secondary outcomes also favored telephone-based CBT. “The intervention was feasible and highly acceptable, yielding an 88% retention rate over the 9-month trial,” Dr. Dobkin and colleagues said.

Compared with other control conditions, treatment-as-usual controls may enhance the effect size of an intervention, the authors noted. In addition, factors such as therapeutic relationship, time, and attention likely contribute to psychotherapy outcomes.
 

Success may hinge on cognitive ability

“The success of this trial highlights the need for further efficacy studies targeting neuropsychiatric manifestations of [Parkinson’s disease] and adds urgency to the discussion over policies regarding access to tele–mental health, especially for vulnerable populations with limited access to in-person mental health services,” Gregory M. Pontone, MD, and Kelly A. Mills, MD, wrote in an accompanying editorial. Dr. Pontone and Dr. Mills are affiliated with Johns Hopkins University in Baltimore.

“Only rudimentary evidence” exists to guide the treatment of depression in patients with Parkinson’s disease, the editorialists said. “Patient preference and tolerability suggest that nonpharmacologic therapies, such as CBT, are preferred as first-line treatment. Yet access to qualified CBT practitioners, especially those with a clinical knowledge of [Parkinson’s disease], is limited.”

Despite its advantages and the encouraging results, CBT may have important limitations as well, they said. Patients require a certain degree of cognitive ability to benefit from CBT, and the prevalence of dementia among patients with Parkinson’s disease is about 30%.

Nevertheless, the trial provided evidence of target engagement. “Though caveats include the single-blind design and potential confounding by time spent with patient and caregiver, the authors demonstrated that improvement was mediated by the mechanism of CBT – a reduction in negative thinking.”

The trial was funded by the Michael J. Fox Foundation for Parkinson’s Research and the Parkinson’s Alliance (Parkinson’s Unity Walk). Dr. Mills disclosed a patent pending for a system for phase-dependent cortical brain stimulation, National Institutes of Health funding, pending funding from the Michael J. Fox Foundation, and commercial research support from Global Kinetics Corporation. Dr. Pontone is a consultant for Acadia Pharmaceuticals.

jremaly@mdedge.com

SOURCE: Dobkin RD et al. Neurology. 2020 Apr 1. doi: 10.1212/WNL.0000000000009292.

Why has deep brain stimulation (DBS) surpassed ablative surgery as the surgical treatment of choice in patients with levodopa-induced dyskinesia (LID)?

Dr. LeWitt: In ablative surgery for LID, a thermo-coagulation lesion is placed in the globus pallidus interna (GPi). This target of therapy was in use before development of DBS as another way to treat involuntary movements complicating control of Parkinson disease with dopaminergic therapy.
 
The use of DBS has replaced ablative surgery in most centers offering functional neurosurgery because DBS offers far more control of the clinical outcome. The lesion created by ablation is a permanent effect, whether desired or not. If a GPi lesion were to be inaccurately placed, or too small or large, there could be consequences that a patient would have to live with. Furthermore, ablative surgery also had an unacceptably high incidence of dysphagia and dysarthria (speaking and swallowing difficulties) when the pallidotomy procedure was carried out bilaterally. Bilateral DBS can sometimes lead to similar problems, but by adjusting stimulation settings (or even shutting off one pulse generator when a patient is feeding or speaking), such outcomes can be avoided. With some of the stimulation devices currently in use, the DBS implanted pulse generator has an option for multiple stimulation settings to be created.

Most patients with Parkinson disease have bilateral involvement and so need both sides of the brain treated for optimal outcomes. Once DBS became available, pallidotomy carried out bilaterally was recognized to pose unacceptable risks for most patients.
 
The efficacy of DBS targeted at the GPi also seems to be better than the clinical results of pallidotomy in the earlier era of functional neurosurgery. Being able to change parameters of electrical stimulation (its location, frequency, pulse width, and current delivery) gives the clinician several tools for enhancing precision to tailor clinical effect and in a manner not achieved from pallidotomy. In the United States and elsewhere, electrical stimulation of GPi and other brain targets is the predominant procedure of functional neurosurgery for movement disorders.

Are there situations where ablative surgery is still considered, and if so, what are they?

Dr. LeWitt: Abblative neurosurgery is not widely used in the U.S. or Europe for movement disorders, though it might be utilized in clinical settings where the expensive DBS electrodes and pulse generators are not routinely available. Furthermore, there are patients who have MRI-incompatible situations and who might opt for lesioning the brain for LID (especially is carried out unilaterally)  In my experience at a U.S. hospital, these cases are currently quite rare since the risks of a thermoablation would seem to be greater than simply implanting an electrode in the brain.

Magnetic resonance-guided focused ultrasound (MRg-FUS) pallidotomy has emerged as an incisionless ablative technique. What are the pros and cons of that treatment?
 
Dr. LeWitt: Using MRg-FUS to create ablative lesions in the brain is a promising new direction for accomplishing an outcome of pallidotomy without the need to penetrate the skull and brain surgically. However, not many treatment centers have acquired equipment for this procedure.
 
The precision of localizing thermal ablations with FUS seems to be much improved over the operative surgical approach – this is because there's real-time MRI guidance that permit the clinician to localize the intended lesion. The methodology of FUS permits good control over the size of the thermocoagulation procedure carried out in the awake patient, who is able to report on any adverse aspects of the localization of the intended lesioning. Whether this new way to achieve pallidotomy will be an improvement over the conventional surgical methods, or whether this procedure (carried out unilaterally) will be equal to DBS outcomes, remains to be studied further.
 
In the best of scenarios, incisionless surgery will have fewer surgery-associated risks. By avoiding the need for devices that have to be inserted in the brain (and the risks and costs that they impose), that's an appealing prospect for future therapeutics of movement disorders like LID.

What do you believe will be the preferred surgical procedure for LID in the future?
 

Dr. LeWitt: Thanks to the long experience with DBS of the GPi and the other benefits this technique provides for control of Parkinson disease, I predict that implanted stimulation electrodes will continue to be a predominant treatment option. As an alternative approach, MRg-FUS is currently limited to unilateral use and has far less long-term clinical experience – it  should be regarded as still in the developmental stage (and is not an FDA-approved use, even though MRg-FUS use for treating tremor through thalamic lesioning is sanctioned). However, with more research experience and, if safe and effective, its ultimate approval, non-surgical GPi lesioning might become an appealing alternative to DBS. Research with GPi MRg-FUS has already had peer-reviewing reporting as to safety and efficacy. Of course, other options for control of LID are being explored, such as more constant delivery of levodopa and drugs specifically targeting mechanisms of involuntary movements.

Why has deep brain stimulation (DBS) surpassed ablative surgery as the surgical treatment of choice in patients with levodopa-induced dyskinesia (LID)?

Dr. LeWitt: In ablative surgery for LID, a thermo-coagulation lesion is placed in the globus pallidus interna (GPi). This target of therapy was in use before development of DBS as another way to treat involuntary movements complicating control of Parkinson disease with dopaminergic therapy.
 
The use of DBS has replaced ablative surgery in most centers offering functional neurosurgery because DBS offers far more control of the clinical outcome. The lesion created by ablation is a permanent effect, whether desired or not. If a GPi lesion were to be inaccurately placed, or too small or large, there could be consequences that a patient would have to live with. Furthermore, ablative surgery also had an unacceptably high incidence of dysphagia and dysarthria (speaking and swallowing difficulties) when the pallidotomy procedure was carried out bilaterally. Bilateral DBS can sometimes lead to similar problems, but by adjusting stimulation settings (or even shutting off one pulse generator when a patient is feeding or speaking), such outcomes can be avoided. With some of the stimulation devices currently in use, the DBS implanted pulse generator has an option for multiple stimulation settings to be created.

Most patients with Parkinson disease have bilateral involvement and so need both sides of the brain treated for optimal outcomes. Once DBS became available, pallidotomy carried out bilaterally was recognized to pose unacceptable risks for most patients.
 
The efficacy of DBS targeted at the GPi also seems to be better than the clinical results of pallidotomy in the earlier era of functional neurosurgery. Being able to change parameters of electrical stimulation (its location, frequency, pulse width, and current delivery) gives the clinician several tools for enhancing precision to tailor clinical effect and in a manner not achieved from pallidotomy. In the United States and elsewhere, electrical stimulation of GPi and other brain targets is the predominant procedure of functional neurosurgery for movement disorders.

Are there situations where ablative surgery is still considered, and if so, what are they?

Dr. LeWitt: Abblative neurosurgery is not widely used in the U.S. or Europe for movement disorders, though it might be utilized in clinical settings where the expensive DBS electrodes and pulse generators are not routinely available. Furthermore, there are patients who have MRI-incompatible situations and who might opt for lesioning the brain for LID (especially is carried out unilaterally)  In my experience at a U.S. hospital, these cases are currently quite rare since the risks of a thermoablation would seem to be greater than simply implanting an electrode in the brain.

Magnetic resonance-guided focused ultrasound (MRg-FUS) pallidotomy has emerged as an incisionless ablative technique. What are the pros and cons of that treatment?
 
Dr. LeWitt: Using MRg-FUS to create ablative lesions in the brain is a promising new direction for accomplishing an outcome of pallidotomy without the need to penetrate the skull and brain surgically. However, not many treatment centers have acquired equipment for this procedure.
 
The precision of localizing thermal ablations with FUS seems to be much improved over the operative surgical approach – this is because there's real-time MRI guidance that permit the clinician to localize the intended lesion. The methodology of FUS permits good control over the size of the thermocoagulation procedure carried out in the awake patient, who is able to report on any adverse aspects of the localization of the intended lesioning. Whether this new way to achieve pallidotomy will be an improvement over the conventional surgical methods, or whether this procedure (carried out unilaterally) will be equal to DBS outcomes, remains to be studied further.
 
In the best of scenarios, incisionless surgery will have fewer surgery-associated risks. By avoiding the need for devices that have to be inserted in the brain (and the risks and costs that they impose), that's an appealing prospect for future therapeutics of movement disorders like LID.

What do you believe will be the preferred surgical procedure for LID in the future?
 

Dr. LeWitt: Thanks to the long experience with DBS of the GPi and the other benefits this technique provides for control of Parkinson disease, I predict that implanted stimulation electrodes will continue to be a predominant treatment option. As an alternative approach, MRg-FUS is currently limited to unilateral use and has far less long-term clinical experience – it  should be regarded as still in the developmental stage (and is not an FDA-approved use, even though MRg-FUS use for treating tremor through thalamic lesioning is sanctioned). However, with more research experience and, if safe and effective, its ultimate approval, non-surgical GPi lesioning might become an appealing alternative to DBS. Research with GPi MRg-FUS has already had peer-reviewing reporting as to safety and efficacy. Of course, other options for control of LID are being explored, such as more constant delivery of levodopa and drugs specifically targeting mechanisms of involuntary movements.

Why has deep brain stimulation (DBS) surpassed ablative surgery as the surgical treatment of choice in patients with levodopa-induced dyskinesia (LID)?

Dr. LeWitt: In ablative surgery for LID, a thermo-coagulation lesion is placed in the globus pallidus interna (GPi). This target of therapy was in use before development of DBS as another way to treat involuntary movements complicating control of Parkinson disease with dopaminergic therapy.
 
The use of DBS has replaced ablative surgery in most centers offering functional neurosurgery because DBS offers far more control of the clinical outcome. The lesion created by ablation is a permanent effect, whether desired or not. If a GPi lesion were to be inaccurately placed, or too small or large, there could be consequences that a patient would have to live with. Furthermore, ablative surgery also had an unacceptably high incidence of dysphagia and dysarthria (speaking and swallowing difficulties) when the pallidotomy procedure was carried out bilaterally. Bilateral DBS can sometimes lead to similar problems, but by adjusting stimulation settings (or even shutting off one pulse generator when a patient is feeding or speaking), such outcomes can be avoided. With some of the stimulation devices currently in use, the DBS implanted pulse generator has an option for multiple stimulation settings to be created.

Most patients with Parkinson disease have bilateral involvement and so need both sides of the brain treated for optimal outcomes. Once DBS became available, pallidotomy carried out bilaterally was recognized to pose unacceptable risks for most patients.
 
The efficacy of DBS targeted at the GPi also seems to be better than the clinical results of pallidotomy in the earlier era of functional neurosurgery. Being able to change parameters of electrical stimulation (its location, frequency, pulse width, and current delivery) gives the clinician several tools for enhancing precision to tailor clinical effect and in a manner not achieved from pallidotomy. In the United States and elsewhere, electrical stimulation of GPi and other brain targets is the predominant procedure of functional neurosurgery for movement disorders.

Are there situations where ablative surgery is still considered, and if so, what are they?

Dr. LeWitt: Abblative neurosurgery is not widely used in the U.S. or Europe for movement disorders, though it might be utilized in clinical settings where the expensive DBS electrodes and pulse generators are not routinely available. Furthermore, there are patients who have MRI-incompatible situations and who might opt for lesioning the brain for LID (especially is carried out unilaterally)  In my experience at a U.S. hospital, these cases are currently quite rare since the risks of a thermoablation would seem to be greater than simply implanting an electrode in the brain.

Magnetic resonance-guided focused ultrasound (MRg-FUS) pallidotomy has emerged as an incisionless ablative technique. What are the pros and cons of that treatment?
 
Dr. LeWitt: Using MRg-FUS to create ablative lesions in the brain is a promising new direction for accomplishing an outcome of pallidotomy without the need to penetrate the skull and brain surgically. However, not many treatment centers have acquired equipment for this procedure.
 
The precision of localizing thermal ablations with FUS seems to be much improved over the operative surgical approach – this is because there's real-time MRI guidance that permit the clinician to localize the intended lesion. The methodology of FUS permits good control over the size of the thermocoagulation procedure carried out in the awake patient, who is able to report on any adverse aspects of the localization of the intended lesioning. Whether this new way to achieve pallidotomy will be an improvement over the conventional surgical methods, or whether this procedure (carried out unilaterally) will be equal to DBS outcomes, remains to be studied further.
 
In the best of scenarios, incisionless surgery will have fewer surgery-associated risks. By avoiding the need for devices that have to be inserted in the brain (and the risks and costs that they impose), that's an appealing prospect for future therapeutics of movement disorders like LID.

What do you believe will be the preferred surgical procedure for LID in the future?
 

Dr. LeWitt: Thanks to the long experience with DBS of the GPi and the other benefits this technique provides for control of Parkinson disease, I predict that implanted stimulation electrodes will continue to be a predominant treatment option. As an alternative approach, MRg-FUS is currently limited to unilateral use and has far less long-term clinical experience – it  should be regarded as still in the developmental stage (and is not an FDA-approved use, even though MRg-FUS use for treating tremor through thalamic lesioning is sanctioned). However, with more research experience and, if safe and effective, its ultimate approval, non-surgical GPi lesioning might become an appealing alternative to DBS. Research with GPi MRg-FUS has already had peer-reviewing reporting as to safety and efficacy. Of course, other options for control of LID are being explored, such as more constant delivery of levodopa and drugs specifically targeting mechanisms of involuntary movements.

recently coauthored the manuscript "Recent Advances in the Development of Experimental Therapeutics for Levodopa-Induced Dyskinesia."* We took a moment to sit down with Mr. Martini to discuss some of the potential therapies for patients with Parkinson disease (PD).

How can targeting serotonergic neurons help control levodopa-induced dyskinesia (LID)?
 
Serotonergic neurons appear to have an interesting relationship with dyskinesia in patients with PD. One potential reason for this might be because the serotonergic neurons possess the molecular machinery to convert L-dopa into dopamine, contributing to dopaminergic transmission in the brain.
 
However, dopaminergic neurons possess auto receptors, which essentially act as an off switch when too much dopamine is being transmitted. This negative feedback loop works to stabilize dopaminergic transmission.
 
When a patient with early PD takes an oral dose of L-dopa, it is converted into dopamine in the central serotonergic neurons and the excess dopamine is buffered by retained dopaminergic neurons.
 
As PD advances, more significant destruction of these dopaminergic terminals means a loss in the capacity to buffer excess dopamine, which in turn can lead to dyskinesia.
 
I believe that there are particularly exciting results in preclinical and clinical studies exploiting this framework. For example, we have learned that there is a synergistic effect on dyskinesia reduction that occurs when agonists of 5-HT1A and 1B receptors are administered to animal models of PD. 
 
This presumably occurs because the serotonergic autoreceptors are being stimulated by the serotonin agonists. This may explain why previous studies using sarizotan, which is only a 5-HT1A agonist, did not show significant LID reduction. More recent clinical studies have taken advantage of this synergistic effect by giving eltoprazine, which is a dual 5-HT1A/1B agonist. Clinical trials with eltoprazine showed significant reduction in LID symptoms on two different clinical scales—the Clinical Dyskinesia Rating Scale and the Rush Dyskinesia Rating Scale.
 
You also discussed alpha-lipoic acid as a treatment option. How can this work to delay the onset of LID?
 
 Alpha-lipoic acid research revolves around the central finding that patients treated with L-dopa have been shown to have enhanced processes of oxidative stress occurring in their brains. 
 
There are a few possible reasons for this reaction. It might be that these patients have lower antioxidant levels or excessive oxidation of dopamine or disruptions in the mitochondrial transport chain. 
 
Other studies have found increased markers of oxidation and neuroinflammation present, which may suggest that monitoring these oxidative stress markers could be useful in some patients with PD who are receiving L-dopa. 
 
Some early studies found that alpha-lipoic acid could reduce reactive oxygen species and spare dopaminergic neurons in primate models of PD.
 
Recently we found more promising results when administering alpha-lipoic acid with L-dopa. Co-treatment had a dose-dependent anti-dyskinetic effect. 
 
When sampling of biomarkers and metabolites was done, the results corroborated the idea that alpha-lipoic acid might reduce oxidative stress and apoptosis to achieve neuroprotection.
 
It is also important to note this distinction with alpha-lipoic acid: among experimental Parkinson therapeutics it might be a disease-modifying agent. This is noteworthy when considering that most other therapies are simply just trying to alleviate symptoms of PD and dyskinesia.
 
More work still needs to be done in this area, including full-scale clinical studies to substantiate these claims in humans. But I do believe that the results to date are exciting. 
 
What other pharmacological approaches to LID look promising?
 
 There is another approach to LID that I believe to be promising, even though it is still a ways off from being clinically developed—it relates to beta-arrestin signaling.
 
Recent studies have elucidated that in addition to their roles as G-protein coupled receptors, dopamine receptors are also capable of signaling through a distinct beta-arrestin2-dependent pathway, in addition to the canonical G-protein pathway.
 
This is important because a lot of traditional dopamine agonists, including L-dopa, signal through dopamine D1/D2 receptors.
 
Other studies have also suggested that this G-protein independent pathway, the beta-arrestin pathway, along with traditional G-protein pathway, are important in regulating downstream responses at dopamine receptors. They play significant roles in converting dopamine signaling into motor function, which sheds new light on the known functions of beta-arrestins.
 
Some promising and exciting preclinical data has emerged, suggesting that beta-arrestin signaling is critical for locomotion in L-dopa and that when it is removed, locomotor responses to L-dopa are decreased and there is an increased propensity towards LID in these models.
 
Further validation for targeting beta-arrestin signaling at the dopamine receptors was provided in primate models of PD, where genetic overexpression of beta-arrestin reduced dyskinesias and rescued locomotion when L-dopa was given. 
 
I think we are at an exciting point in terms of the number of promising avenues that we have in devising potential strategies for treating LID. I think that innovations in this area have progressed significantly in recent years and I hope that at least a few of these experimental therapies might end up helping patients in the future.
 
*Martini ML, Neifert SN, Mocco J, et al. Recent Advances in the Development of Experimental Therapeutics for Levodopa-Induced Dyskinesia. J Mov Disord. 2019;12
 

recently coauthored the manuscript "Recent Advances in the Development of Experimental Therapeutics for Levodopa-Induced Dyskinesia."* We took a moment to sit down with Mr. Martini to discuss some of the potential therapies for patients with Parkinson disease (PD).

How can targeting serotonergic neurons help control levodopa-induced dyskinesia (LID)?
 
Serotonergic neurons appear to have an interesting relationship with dyskinesia in patients with PD. One potential reason for this might be because the serotonergic neurons possess the molecular machinery to convert L-dopa into dopamine, contributing to dopaminergic transmission in the brain.
 
However, dopaminergic neurons possess auto receptors, which essentially act as an off switch when too much dopamine is being transmitted. This negative feedback loop works to stabilize dopaminergic transmission.
 
When a patient with early PD takes an oral dose of L-dopa, it is converted into dopamine in the central serotonergic neurons and the excess dopamine is buffered by retained dopaminergic neurons.
 
As PD advances, more significant destruction of these dopaminergic terminals means a loss in the capacity to buffer excess dopamine, which in turn can lead to dyskinesia.
 
I believe that there are particularly exciting results in preclinical and clinical studies exploiting this framework. For example, we have learned that there is a synergistic effect on dyskinesia reduction that occurs when agonists of 5-HT1A and 1B receptors are administered to animal models of PD. 
 
This presumably occurs because the serotonergic autoreceptors are being stimulated by the serotonin agonists. This may explain why previous studies using sarizotan, which is only a 5-HT1A agonist, did not show significant LID reduction. More recent clinical studies have taken advantage of this synergistic effect by giving eltoprazine, which is a dual 5-HT1A/1B agonist. Clinical trials with eltoprazine showed significant reduction in LID symptoms on two different clinical scales—the Clinical Dyskinesia Rating Scale and the Rush Dyskinesia Rating Scale.
 
You also discussed alpha-lipoic acid as a treatment option. How can this work to delay the onset of LID?
 
 Alpha-lipoic acid research revolves around the central finding that patients treated with L-dopa have been shown to have enhanced processes of oxidative stress occurring in their brains. 
 
There are a few possible reasons for this reaction. It might be that these patients have lower antioxidant levels or excessive oxidation of dopamine or disruptions in the mitochondrial transport chain. 
 
Other studies have found increased markers of oxidation and neuroinflammation present, which may suggest that monitoring these oxidative stress markers could be useful in some patients with PD who are receiving L-dopa. 
 
Some early studies found that alpha-lipoic acid could reduce reactive oxygen species and spare dopaminergic neurons in primate models of PD.
 
Recently we found more promising results when administering alpha-lipoic acid with L-dopa. Co-treatment had a dose-dependent anti-dyskinetic effect. 
 
When sampling of biomarkers and metabolites was done, the results corroborated the idea that alpha-lipoic acid might reduce oxidative stress and apoptosis to achieve neuroprotection.
 
It is also important to note this distinction with alpha-lipoic acid: among experimental Parkinson therapeutics it might be a disease-modifying agent. This is noteworthy when considering that most other therapies are simply just trying to alleviate symptoms of PD and dyskinesia.
 
More work still needs to be done in this area, including full-scale clinical studies to substantiate these claims in humans. But I do believe that the results to date are exciting. 
 
What other pharmacological approaches to LID look promising?
 
 There is another approach to LID that I believe to be promising, even though it is still a ways off from being clinically developed—it relates to beta-arrestin signaling.
 
Recent studies have elucidated that in addition to their roles as G-protein coupled receptors, dopamine receptors are also capable of signaling through a distinct beta-arrestin2-dependent pathway, in addition to the canonical G-protein pathway.
 
This is important because a lot of traditional dopamine agonists, including L-dopa, signal through dopamine D1/D2 receptors.
 
Other studies have also suggested that this G-protein independent pathway, the beta-arrestin pathway, along with traditional G-protein pathway, are important in regulating downstream responses at dopamine receptors. They play significant roles in converting dopamine signaling into motor function, which sheds new light on the known functions of beta-arrestins.
 
Some promising and exciting preclinical data has emerged, suggesting that beta-arrestin signaling is critical for locomotion in L-dopa and that when it is removed, locomotor responses to L-dopa are decreased and there is an increased propensity towards LID in these models.
 
Further validation for targeting beta-arrestin signaling at the dopamine receptors was provided in primate models of PD, where genetic overexpression of beta-arrestin reduced dyskinesias and rescued locomotion when L-dopa was given. 
 
I think we are at an exciting point in terms of the number of promising avenues that we have in devising potential strategies for treating LID. I think that innovations in this area have progressed significantly in recent years and I hope that at least a few of these experimental therapies might end up helping patients in the future.
 
*Martini ML, Neifert SN, Mocco J, et al. Recent Advances in the Development of Experimental Therapeutics for Levodopa-Induced Dyskinesia. J Mov Disord. 2019;12
 

recently coauthored the manuscript "Recent Advances in the Development of Experimental Therapeutics for Levodopa-Induced Dyskinesia."* We took a moment to sit down with Mr. Martini to discuss some of the potential therapies for patients with Parkinson disease (PD).

How can targeting serotonergic neurons help control levodopa-induced dyskinesia (LID)?
 
Serotonergic neurons appear to have an interesting relationship with dyskinesia in patients with PD. One potential reason for this might be because the serotonergic neurons possess the molecular machinery to convert L-dopa into dopamine, contributing to dopaminergic transmission in the brain.
 
However, dopaminergic neurons possess auto receptors, which essentially act as an off switch when too much dopamine is being transmitted. This negative feedback loop works to stabilize dopaminergic transmission.
 
When a patient with early PD takes an oral dose of L-dopa, it is converted into dopamine in the central serotonergic neurons and the excess dopamine is buffered by retained dopaminergic neurons.
 
As PD advances, more significant destruction of these dopaminergic terminals means a loss in the capacity to buffer excess dopamine, which in turn can lead to dyskinesia.
 
I believe that there are particularly exciting results in preclinical and clinical studies exploiting this framework. For example, we have learned that there is a synergistic effect on dyskinesia reduction that occurs when agonists of 5-HT1A and 1B receptors are administered to animal models of PD. 
 
This presumably occurs because the serotonergic autoreceptors are being stimulated by the serotonin agonists. This may explain why previous studies using sarizotan, which is only a 5-HT1A agonist, did not show significant LID reduction. More recent clinical studies have taken advantage of this synergistic effect by giving eltoprazine, which is a dual 5-HT1A/1B agonist. Clinical trials with eltoprazine showed significant reduction in LID symptoms on two different clinical scales—the Clinical Dyskinesia Rating Scale and the Rush Dyskinesia Rating Scale.
 
You also discussed alpha-lipoic acid as a treatment option. How can this work to delay the onset of LID?
 
 Alpha-lipoic acid research revolves around the central finding that patients treated with L-dopa have been shown to have enhanced processes of oxidative stress occurring in their brains. 
 
There are a few possible reasons for this reaction. It might be that these patients have lower antioxidant levels or excessive oxidation of dopamine or disruptions in the mitochondrial transport chain. 
 
Other studies have found increased markers of oxidation and neuroinflammation present, which may suggest that monitoring these oxidative stress markers could be useful in some patients with PD who are receiving L-dopa. 
 
Some early studies found that alpha-lipoic acid could reduce reactive oxygen species and spare dopaminergic neurons in primate models of PD.
 
Recently we found more promising results when administering alpha-lipoic acid with L-dopa. Co-treatment had a dose-dependent anti-dyskinetic effect. 
 
When sampling of biomarkers and metabolites was done, the results corroborated the idea that alpha-lipoic acid might reduce oxidative stress and apoptosis to achieve neuroprotection.
 
It is also important to note this distinction with alpha-lipoic acid: among experimental Parkinson therapeutics it might be a disease-modifying agent. This is noteworthy when considering that most other therapies are simply just trying to alleviate symptoms of PD and dyskinesia.
 
More work still needs to be done in this area, including full-scale clinical studies to substantiate these claims in humans. But I do believe that the results to date are exciting. 
 
What other pharmacological approaches to LID look promising?
 
 There is another approach to LID that I believe to be promising, even though it is still a ways off from being clinically developed—it relates to beta-arrestin signaling.
 
Recent studies have elucidated that in addition to their roles as G-protein coupled receptors, dopamine receptors are also capable of signaling through a distinct beta-arrestin2-dependent pathway, in addition to the canonical G-protein pathway.
 
This is important because a lot of traditional dopamine agonists, including L-dopa, signal through dopamine D1/D2 receptors.
 
Other studies have also suggested that this G-protein independent pathway, the beta-arrestin pathway, along with traditional G-protein pathway, are important in regulating downstream responses at dopamine receptors. They play significant roles in converting dopamine signaling into motor function, which sheds new light on the known functions of beta-arrestins.
 
Some promising and exciting preclinical data has emerged, suggesting that beta-arrestin signaling is critical for locomotion in L-dopa and that when it is removed, locomotor responses to L-dopa are decreased and there is an increased propensity towards LID in these models.
 
Further validation for targeting beta-arrestin signaling at the dopamine receptors was provided in primate models of PD, where genetic overexpression of beta-arrestin reduced dyskinesias and rescued locomotion when L-dopa was given. 
 
I think we are at an exciting point in terms of the number of promising avenues that we have in devising potential strategies for treating LID. I think that innovations in this area have progressed significantly in recent years and I hope that at least a few of these experimental therapies might end up helping patients in the future.
 
*Martini ML, Neifert SN, Mocco J, et al. Recent Advances in the Development of Experimental Therapeutics for Levodopa-Induced Dyskinesia. J Mov Disord. 2019;12
 

How do we recognize and explain the necessity for a peak dose to patients with levodopa-induced dyskinesia (LID)?
 
The way I usually do it with my patients is I draw a graph. On the X axis I have time; on the Y axis I have levodopa levels. Then I show them on the graph a sinusoidal wave, displaying how, if they take their medication at 8 in the morning, the medication will grow in terms of concentration and then it will wear off.
 
With the sinusoidal wave I'm able to illustrate that at the peak a patient may have what we call "peak-dose dyskinesia." Typically for patients that's anywhere from 30 minutes to 45 minutes after they take their carbidopa/levodopa medication.
 
In terms of recognizing those symptoms, I usually spend some time with a patient describing what dyskinesia looks or feels like. There are certain cases where patients are unaware of their dyskinetic movements, when instead their caregiver, spouse, or partner are the ones actually recognizing the movements.
 
Typically, we talk about facial movements or lip/jaw movements and we can talk about upper extremity truncal writhing or hyperkinetic movements.
 
Sometimes, I'll have the patient come to the clinic having not taken their medication and then we evaluate them and have them take their medicine. About 30-45 minutes later we reevaluate the patient, which is when we can see the movements and have the patient look at themselves in the mirror to see what we're talking about, or at least explain movements to the caregiver.

 
Ultimately what we are trying to do is link the timing of medication and the timing of these side effects to help the patient and their family member understand the nature of what these symptoms are and when they're happening in relation to the medication that they're taking.
 
How can practitioners assess patients as their LID might become unpredictable?
 
I think the first step is to recognize that there are certain patients with Parkinson disease who are more likely to have adverse responses to levodopa. They're typically younger and they usually have other symptoms they are concerned about.
 
For example, it is very common for the patient to describe feeling stressed. I have had a number of patients tell me that when they're having anxiety or stress-related issues, such as at work or in their interpersonal relationships, that their dyskinesia might come on and progress a little bit more suddenly or unpredictably outside of that window when we typically expect it to peak.
 
Other triggers could be food. For instance, if a patient has changed their diet or changed the timing of their food intake, there may be issues related to gastric emptying or gastrointestinal symptoms that may influence the onset of these symptoms.

 
What we try to do is recognize the movements and then associate them with the environment or the timing behind the medication. When these things happen outside of the regular time when they're accustomed to getting them, we talk about these as unpredictable movements.
 
The other side effect is that patients can often have dystonia, or a forced muscle contraction. We are not only focused on the dyskinesia movement; dystonic movements are important as well.
 
Overall, I think practitioners can explain to patients the difference between these predictable and unpredictable movements. Additionally, we must help patients better recognize their symptoms and maybe the triggers for them, so that they may better manage them over time.
 
What are some aspects of LID that are most important to discuss with patients before a treatment?
 
The most important thing to talk about is the rationale for why a person would want to initiate levodopa or another medication.
 
Usually when a clinician is talking with a patient about pharmacotherapy they explain symptoms and how the individuals quality of life would improve if we treat them with levodopa.
 
We spend time explaining that the dose that's going to be required to get optimal control of their symptoms may differ in one person from another. And part of that dose selection is the fact that we're going to have to balance between not enough medication to too much medication.
 
So, I think the most important thing to discuss with patients is developing a strategy to come up with an individualized plan for medication management and explain to the patients the idea of on and off, explaining the idea of things that could interfere with medication, such as food or timing of medication use because of sleeping or changes to their day.
 
Basically, we are trying to give patients the framework for why we're dosing at certain times of the day regularly, why we're starting at a certain dose, and why we gradually increase the dose until we find resolution of their symptoms. We might explain why we may gradually reduce the dose if they are having symptoms like LID, and then why we may add other medications if they are experiencing LID. Also, we explain how and why we might not reduce the dose if a dose reduction would likely trigger worse symptoms.
 
Our aim is to give patients an outline of on/off factors that can affect drug availability and explain the long-term treatment goal, which is to optimize their motor symptoms to give them the best quality of life.

How do we recognize and explain the necessity for a peak dose to patients with levodopa-induced dyskinesia (LID)?
 
The way I usually do it with my patients is I draw a graph. On the X axis I have time; on the Y axis I have levodopa levels. Then I show them on the graph a sinusoidal wave, displaying how, if they take their medication at 8 in the morning, the medication will grow in terms of concentration and then it will wear off.
 
With the sinusoidal wave I'm able to illustrate that at the peak a patient may have what we call "peak-dose dyskinesia." Typically for patients that's anywhere from 30 minutes to 45 minutes after they take their carbidopa/levodopa medication.
 
In terms of recognizing those symptoms, I usually spend some time with a patient describing what dyskinesia looks or feels like. There are certain cases where patients are unaware of their dyskinetic movements, when instead their caregiver, spouse, or partner are the ones actually recognizing the movements.
 
Typically, we talk about facial movements or lip/jaw movements and we can talk about upper extremity truncal writhing or hyperkinetic movements.
 
Sometimes, I'll have the patient come to the clinic having not taken their medication and then we evaluate them and have them take their medicine. About 30-45 minutes later we reevaluate the patient, which is when we can see the movements and have the patient look at themselves in the mirror to see what we're talking about, or at least explain movements to the caregiver.

 
Ultimately what we are trying to do is link the timing of medication and the timing of these side effects to help the patient and their family member understand the nature of what these symptoms are and when they're happening in relation to the medication that they're taking.
 
How can practitioners assess patients as their LID might become unpredictable?
 
I think the first step is to recognize that there are certain patients with Parkinson disease who are more likely to have adverse responses to levodopa. They're typically younger and they usually have other symptoms they are concerned about.
 
For example, it is very common for the patient to describe feeling stressed. I have had a number of patients tell me that when they're having anxiety or stress-related issues, such as at work or in their interpersonal relationships, that their dyskinesia might come on and progress a little bit more suddenly or unpredictably outside of that window when we typically expect it to peak.
 
Other triggers could be food. For instance, if a patient has changed their diet or changed the timing of their food intake, there may be issues related to gastric emptying or gastrointestinal symptoms that may influence the onset of these symptoms.

 
What we try to do is recognize the movements and then associate them with the environment or the timing behind the medication. When these things happen outside of the regular time when they're accustomed to getting them, we talk about these as unpredictable movements.
 
The other side effect is that patients can often have dystonia, or a forced muscle contraction. We are not only focused on the dyskinesia movement; dystonic movements are important as well.
 
Overall, I think practitioners can explain to patients the difference between these predictable and unpredictable movements. Additionally, we must help patients better recognize their symptoms and maybe the triggers for them, so that they may better manage them over time.
 
What are some aspects of LID that are most important to discuss with patients before a treatment?
 
The most important thing to talk about is the rationale for why a person would want to initiate levodopa or another medication.
 
Usually when a clinician is talking with a patient about pharmacotherapy they explain symptoms and how the individuals quality of life would improve if we treat them with levodopa.
 
We spend time explaining that the dose that's going to be required to get optimal control of their symptoms may differ in one person from another. And part of that dose selection is the fact that we're going to have to balance between not enough medication to too much medication.
 
So, I think the most important thing to discuss with patients is developing a strategy to come up with an individualized plan for medication management and explain to the patients the idea of on and off, explaining the idea of things that could interfere with medication, such as food or timing of medication use because of sleeping or changes to their day.
 
Basically, we are trying to give patients the framework for why we're dosing at certain times of the day regularly, why we're starting at a certain dose, and why we gradually increase the dose until we find resolution of their symptoms. We might explain why we may gradually reduce the dose if they are having symptoms like LID, and then why we may add other medications if they are experiencing LID. Also, we explain how and why we might not reduce the dose if a dose reduction would likely trigger worse symptoms.
 
Our aim is to give patients an outline of on/off factors that can affect drug availability and explain the long-term treatment goal, which is to optimize their motor symptoms to give them the best quality of life.

How do we recognize and explain the necessity for a peak dose to patients with levodopa-induced dyskinesia (LID)?
 
The way I usually do it with my patients is I draw a graph. On the X axis I have time; on the Y axis I have levodopa levels. Then I show them on the graph a sinusoidal wave, displaying how, if they take their medication at 8 in the morning, the medication will grow in terms of concentration and then it will wear off.
 
With the sinusoidal wave I'm able to illustrate that at the peak a patient may have what we call "peak-dose dyskinesia." Typically for patients that's anywhere from 30 minutes to 45 minutes after they take their carbidopa/levodopa medication.
 
In terms of recognizing those symptoms, I usually spend some time with a patient describing what dyskinesia looks or feels like. There are certain cases where patients are unaware of their dyskinetic movements, when instead their caregiver, spouse, or partner are the ones actually recognizing the movements.
 
Typically, we talk about facial movements or lip/jaw movements and we can talk about upper extremity truncal writhing or hyperkinetic movements.
 
Sometimes, I'll have the patient come to the clinic having not taken their medication and then we evaluate them and have them take their medicine. About 30-45 minutes later we reevaluate the patient, which is when we can see the movements and have the patient look at themselves in the mirror to see what we're talking about, or at least explain movements to the caregiver.

 
Ultimately what we are trying to do is link the timing of medication and the timing of these side effects to help the patient and their family member understand the nature of what these symptoms are and when they're happening in relation to the medication that they're taking.
 
How can practitioners assess patients as their LID might become unpredictable?
 
I think the first step is to recognize that there are certain patients with Parkinson disease who are more likely to have adverse responses to levodopa. They're typically younger and they usually have other symptoms they are concerned about.
 
For example, it is very common for the patient to describe feeling stressed. I have had a number of patients tell me that when they're having anxiety or stress-related issues, such as at work or in their interpersonal relationships, that their dyskinesia might come on and progress a little bit more suddenly or unpredictably outside of that window when we typically expect it to peak.
 
Other triggers could be food. For instance, if a patient has changed their diet or changed the timing of their food intake, there may be issues related to gastric emptying or gastrointestinal symptoms that may influence the onset of these symptoms.

 
What we try to do is recognize the movements and then associate them with the environment or the timing behind the medication. When these things happen outside of the regular time when they're accustomed to getting them, we talk about these as unpredictable movements.
 
The other side effect is that patients can often have dystonia, or a forced muscle contraction. We are not only focused on the dyskinesia movement; dystonic movements are important as well.
 
Overall, I think practitioners can explain to patients the difference between these predictable and unpredictable movements. Additionally, we must help patients better recognize their symptoms and maybe the triggers for them, so that they may better manage them over time.
 
What are some aspects of LID that are most important to discuss with patients before a treatment?
 
The most important thing to talk about is the rationale for why a person would want to initiate levodopa or another medication.
 
Usually when a clinician is talking with a patient about pharmacotherapy they explain symptoms and how the individuals quality of life would improve if we treat them with levodopa.
 
We spend time explaining that the dose that's going to be required to get optimal control of their symptoms may differ in one person from another. And part of that dose selection is the fact that we're going to have to balance between not enough medication to too much medication.
 
So, I think the most important thing to discuss with patients is developing a strategy to come up with an individualized plan for medication management and explain to the patients the idea of on and off, explaining the idea of things that could interfere with medication, such as food or timing of medication use because of sleeping or changes to their day.
 
Basically, we are trying to give patients the framework for why we're dosing at certain times of the day regularly, why we're starting at a certain dose, and why we gradually increase the dose until we find resolution of their symptoms. We might explain why we may gradually reduce the dose if they are having symptoms like LID, and then why we may add other medications if they are experiencing LID. Also, we explain how and why we might not reduce the dose if a dose reduction would likely trigger worse symptoms.
 
Our aim is to give patients an outline of on/off factors that can affect drug availability and explain the long-term treatment goal, which is to optimize their motor symptoms to give them the best quality of life.

David Charles, MD, and Thomas Davis, MD, of the Vanderbilt University Department of Neurology, recently spoke with Neurology Reviews about the treatment pipeline and latest research in levodopa-induced dyskinesia in Parkinson's disease.

How is the treatment pipeline advancing for different types of levodopa-induced dyskinesia (LID)?
 
Dr. Thomas Davis: Dyskinesia has traditionally been hard to quantify, and we have been lacking any US Food and Drug Administration (FDA)-approved anti-dyskinesia drugs. The pipeline has historically been strongest for wearing-off because it is easier to measure on time than to quantify involuntary movements.

The Unified Dyskinesia Rating Scale (UDysRS), released in 2008 by the Movement Disorder Society, provided a standardized scale that allowed dyskinesia clinical trials to move forward. The UDysRS was used as the primary outcome for the extended release amantadine capsule study. This was important because it demonstrated the possibility of a successful clinical trial design to get a drug approved for dyskinesia, which will encourage others to test more potential new treatments.
 
What is the status of research on deep brain stimulation (DBS) for Parkinson's disease, and when might it be considered?
 
Dr. David Charles: This is one of the areas of research that we're focused on here at Vanderbilt. All 3 of the FDA-approved device manufacturers have been conducting research in technology refinement and improvements. These advances include not only patient programmers and physician programmers, but also new sensing capability and lead designs. Some of the manufacturers now have leads that allow the physician to steer the current in one direction or another, where traditionally the current has been delivered in a circumferential contact that's shaped like a cylinder, where the energy is transmitted 360 degrees from the lead. The new designs allow you to steer the current hopefully toward areas that provide more efficacy and away from areas that cause side effects. Even more exciting is the emerging sensing capability that may allow the development of stimulating technology that is responsive to fluctuating symptoms. There is keen research interest in understanding whether a device could detect a specific neuronal firing pattern and then respond with an individually tailored stimulation to improve symptoms as needed. Will the next generation of deep brain stimulating devices detect the pattern and deliver energy in a more targeted and precise way, responsive to what it's sensing from the patient's brain? I think that's an area of research that's really exciting.
 
In regard to when it might be considered: The ability to steer the current is already available in 2 of the 3 systems that are on the market today. Having current that is steerable in all 3 will be coming in the not too distant future. The available devices already have improved programming platforms for health care providers as well.
 
Our research at Vanderbilt is focused on DBS in early-stage Parkinson's disease. There is a paper published in Neurology that reports Class II evidencet hat DBS applied in early-stage Parkinson's disease slows the progression of tremor. This is exciting because none of the available treatments change the progression of disease—they're currently accepted as symptomatic therapies only. In this publication, we report that participants receiving DBS in the very earliest stages of Parkinson's disease it may slow the progression of rest tremor. We now have approval from the FDA to conduct a large-scale phase 3, multicenter, clinical trial of DBS in early-stage Parkinson's disease, with the primary endpoint focused on slowing progression of tremor, a cardinal feature of the disease. This upcoming trial is approved by the FDA as a pivotal trial, meaning that the findings could potentially be used to change the labeling of DBS devices. Our goal is to obtain Class I evidence of slowing the progression of tremor or other elements of the disease.
 
Dr. Thomas Davis: If you are a device manufacturer for DBS it is natural for you to aim to make better devices, better batteries, better programming, and better electrodes than your competitor. That's really where the industry-based research is right now. Clinicians are still determining which device is the best candidate, where the best target in the brain is, and when to use DBS.

When would a health care practitioner decide to try frequent smaller dosages or immediate-release formulations of dopaminergic drugs to control levodopa-induced dyskinesia (LID), compared with non-dopaminergic treatments that are available? What are some pros and cons of each approach?
 
Dr. David Charles: If you have a patient who's already on levodopa, it's not uncommon that—separate from the way we prescribe the medicine—the patients experiment with their medicine to some degree. At the very least, people occasionally forget to take a dose and they feel the effect of a missed dose. They may take an extra dose or an extra half dose, particularly if they feel that the last dose isn't working as well, or in the event they have some special occasion coming up. 
 
Over time, patients and physicians learn that sometimes smaller, more frequent dosing of levodopa can be a helpful strategy for certain individuals. One advantage is that it's the medication that the patient is already taking, and they're just simply breaking tablets. Many pharmacies will break tablets for patients so they can take some smaller doses more frequently. Obviously, there can be downsides to that, such as it becoming harder to remember to take more frequent doses.
 
Dr. Thomas Davis: I would agree that the biggest advantage of taking more frequent, smaller doses is that it's cheaper than adding an adjunct or moving to a more invasive therapy.  More frequent smaller doses of levodopa also generally has no side effects because if you're taking 2 carbidopa/levodopa 3 times a day and you're tolerating it, but you're having peak dose problems, you can then switch to 1.5 tablets 4 times a day. It involves more work and planning, but it's no more total medication than the patient is taking already, so this strategy usually does not have any unexpected side effects. It really boils down to how much work the patient wants to put in, how adherent they are to medication dosing, and whether they want to add another medication.
 
Most of the adjunctive medications to treat motor fluctuations are approved to improve on-time in Parkinson's disease patients with wearing off. These include the monoamine oxidase inhibitors, COMT inhibitors, and adenosine A2A antagonists. For treatment of dyskinesia, only the extended release capsule formulation of amantadine has FDA approval, although all formulations are approved for Parkinson's disease and are used clinically to dampen dyskinesia. How long to try these strategies before moving to one of the more advanced therapies, like DBS or jejunal infusion of levodopa, is not clear. It's great to have options, but it makes the decisions a lot harder.
 
Dr. David Charles: Dr. Davis raised the question of what medicine to choose, and what's your next choice in a patient who's having wearing-off dyskinesia or LID and so forth. There is an increasing number of options for those mid-stage patients. The pitfall is feeling that you have to try every available medication and combination before moving to a more advanced therapy.  The physician risks churning through the various combinations for so long that the benefit of an advanced therapy becomes shortened or lost altogether. 
 
Take epilepsy, for example. In operative candidates, surgery is often more beneficial when applied earlier. There's solid data to support that adding on multiple anti-epileptics medications is not always helpful. Continuing to add or change medications can actually diminish returns, particularly in a person who could receive benefit from surgery for epilepsy. 
 
I get the sense that the same may be true for dyskinesia. In clinical practice, we often receive DBS referrals when a patient's community-based physician has tried various medications and combination therapies until the point that the patient and the physician have become totally frustrated. By the time they are referred, the patient may benefit from DBS, but not nearly as well and as for long as they could have if they had received it earlier. We as physicians have to be mindful that while we have these increasing number of options—which is a good thing for both patients and physicians—that we don't continue to use them to the point that it takes away the option of more advanced therapies for appropriate candidates.
 
Metabotropic glutamate (mGlu) receptors have been receiving attention as potential therapeutic targets for LID. How do these compare with other receptors such as N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA)?
 
Dr. Thomas Davis: NMDA and AMPA are traditional ionotropic receptors, meaning that they are ligand gated, that they are almost exclusively excitatory, and that they generally have to do with the flow of potassium. 
 
mGlu receptors are protein coupled receptors. They have more elaborate action and may be either excitatory or inhibitory. Though mGlu, NMDA, and AMPA are completely different, they are all activated by glutamate. Pharmacologically utilizing the mGlu receptors is a relatively new and novel idea. Specifically, mGlu-5 receptors have received the most attention as potentially having an anti-parkinsonian effect and possibly dampening dyskinesia. The mGlu-5 receptors are an attractive target because they are concentrated in the striatum, as opposed to other glutamatergic receptors that are more diffusely located. It was felt that mGlu-5 modulators would be more specific and have less of the potential adverse effects of other glutamates. Most drugs that we think of affecting glutamate, like amantadine and memantine (used for Alzheimer's disease), have some NMDA antagonist effect, but this is relatively mild. 

David Charles, MD, and Thomas Davis, MD, of the Vanderbilt University Department of Neurology, recently spoke with Neurology Reviews about the treatment pipeline and latest research in levodopa-induced dyskinesia in Parkinson's disease.

How is the treatment pipeline advancing for different types of levodopa-induced dyskinesia (LID)?
 
Dr. Thomas Davis: Dyskinesia has traditionally been hard to quantify, and we have been lacking any US Food and Drug Administration (FDA)-approved anti-dyskinesia drugs. The pipeline has historically been strongest for wearing-off because it is easier to measure on time than to quantify involuntary movements.

The Unified Dyskinesia Rating Scale (UDysRS), released in 2008 by the Movement Disorder Society, provided a standardized scale that allowed dyskinesia clinical trials to move forward. The UDysRS was used as the primary outcome for the extended release amantadine capsule study. This was important because it demonstrated the possibility of a successful clinical trial design to get a drug approved for dyskinesia, which will encourage others to test more potential new treatments.
 
What is the status of research on deep brain stimulation (DBS) for Parkinson's disease, and when might it be considered?
 
Dr. David Charles: This is one of the areas of research that we're focused on here at Vanderbilt. All 3 of the FDA-approved device manufacturers have been conducting research in technology refinement and improvements. These advances include not only patient programmers and physician programmers, but also new sensing capability and lead designs. Some of the manufacturers now have leads that allow the physician to steer the current in one direction or another, where traditionally the current has been delivered in a circumferential contact that's shaped like a cylinder, where the energy is transmitted 360 degrees from the lead. The new designs allow you to steer the current hopefully toward areas that provide more efficacy and away from areas that cause side effects. Even more exciting is the emerging sensing capability that may allow the development of stimulating technology that is responsive to fluctuating symptoms. There is keen research interest in understanding whether a device could detect a specific neuronal firing pattern and then respond with an individually tailored stimulation to improve symptoms as needed. Will the next generation of deep brain stimulating devices detect the pattern and deliver energy in a more targeted and precise way, responsive to what it's sensing from the patient's brain? I think that's an area of research that's really exciting.
 
In regard to when it might be considered: The ability to steer the current is already available in 2 of the 3 systems that are on the market today. Having current that is steerable in all 3 will be coming in the not too distant future. The available devices already have improved programming platforms for health care providers as well.
 
Our research at Vanderbilt is focused on DBS in early-stage Parkinson's disease. There is a paper published in Neurology that reports Class II evidencet hat DBS applied in early-stage Parkinson's disease slows the progression of tremor. This is exciting because none of the available treatments change the progression of disease—they're currently accepted as symptomatic therapies only. In this publication, we report that participants receiving DBS in the very earliest stages of Parkinson's disease it may slow the progression of rest tremor. We now have approval from the FDA to conduct a large-scale phase 3, multicenter, clinical trial of DBS in early-stage Parkinson's disease, with the primary endpoint focused on slowing progression of tremor, a cardinal feature of the disease. This upcoming trial is approved by the FDA as a pivotal trial, meaning that the findings could potentially be used to change the labeling of DBS devices. Our goal is to obtain Class I evidence of slowing the progression of tremor or other elements of the disease.
 
Dr. Thomas Davis: If you are a device manufacturer for DBS it is natural for you to aim to make better devices, better batteries, better programming, and better electrodes than your competitor. That's really where the industry-based research is right now. Clinicians are still determining which device is the best candidate, where the best target in the brain is, and when to use DBS.

When would a health care practitioner decide to try frequent smaller dosages or immediate-release formulations of dopaminergic drugs to control levodopa-induced dyskinesia (LID), compared with non-dopaminergic treatments that are available? What are some pros and cons of each approach?
 
Dr. David Charles: If you have a patient who's already on levodopa, it's not uncommon that—separate from the way we prescribe the medicine—the patients experiment with their medicine to some degree. At the very least, people occasionally forget to take a dose and they feel the effect of a missed dose. They may take an extra dose or an extra half dose, particularly if they feel that the last dose isn't working as well, or in the event they have some special occasion coming up. 
 
Over time, patients and physicians learn that sometimes smaller, more frequent dosing of levodopa can be a helpful strategy for certain individuals. One advantage is that it's the medication that the patient is already taking, and they're just simply breaking tablets. Many pharmacies will break tablets for patients so they can take some smaller doses more frequently. Obviously, there can be downsides to that, such as it becoming harder to remember to take more frequent doses.
 
Dr. Thomas Davis: I would agree that the biggest advantage of taking more frequent, smaller doses is that it's cheaper than adding an adjunct or moving to a more invasive therapy.  More frequent smaller doses of levodopa also generally has no side effects because if you're taking 2 carbidopa/levodopa 3 times a day and you're tolerating it, but you're having peak dose problems, you can then switch to 1.5 tablets 4 times a day. It involves more work and planning, but it's no more total medication than the patient is taking already, so this strategy usually does not have any unexpected side effects. It really boils down to how much work the patient wants to put in, how adherent they are to medication dosing, and whether they want to add another medication.
 
Most of the adjunctive medications to treat motor fluctuations are approved to improve on-time in Parkinson's disease patients with wearing off. These include the monoamine oxidase inhibitors, COMT inhibitors, and adenosine A2A antagonists. For treatment of dyskinesia, only the extended release capsule formulation of amantadine has FDA approval, although all formulations are approved for Parkinson's disease and are used clinically to dampen dyskinesia. How long to try these strategies before moving to one of the more advanced therapies, like DBS or jejunal infusion of levodopa, is not clear. It's great to have options, but it makes the decisions a lot harder.
 
Dr. David Charles: Dr. Davis raised the question of what medicine to choose, and what's your next choice in a patient who's having wearing-off dyskinesia or LID and so forth. There is an increasing number of options for those mid-stage patients. The pitfall is feeling that you have to try every available medication and combination before moving to a more advanced therapy.  The physician risks churning through the various combinations for so long that the benefit of an advanced therapy becomes shortened or lost altogether. 
 
Take epilepsy, for example. In operative candidates, surgery is often more beneficial when applied earlier. There's solid data to support that adding on multiple anti-epileptics medications is not always helpful. Continuing to add or change medications can actually diminish returns, particularly in a person who could receive benefit from surgery for epilepsy. 
 
I get the sense that the same may be true for dyskinesia. In clinical practice, we often receive DBS referrals when a patient's community-based physician has tried various medications and combination therapies until the point that the patient and the physician have become totally frustrated. By the time they are referred, the patient may benefit from DBS, but not nearly as well and as for long as they could have if they had received it earlier. We as physicians have to be mindful that while we have these increasing number of options—which is a good thing for both patients and physicians—that we don't continue to use them to the point that it takes away the option of more advanced therapies for appropriate candidates.
 
Metabotropic glutamate (mGlu) receptors have been receiving attention as potential therapeutic targets for LID. How do these compare with other receptors such as N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA)?
 
Dr. Thomas Davis: NMDA and AMPA are traditional ionotropic receptors, meaning that they are ligand gated, that they are almost exclusively excitatory, and that they generally have to do with the flow of potassium. 
 
mGlu receptors are protein coupled receptors. They have more elaborate action and may be either excitatory or inhibitory. Though mGlu, NMDA, and AMPA are completely different, they are all activated by glutamate. Pharmacologically utilizing the mGlu receptors is a relatively new and novel idea. Specifically, mGlu-5 receptors have received the most attention as potentially having an anti-parkinsonian effect and possibly dampening dyskinesia. The mGlu-5 receptors are an attractive target because they are concentrated in the striatum, as opposed to other glutamatergic receptors that are more diffusely located. It was felt that mGlu-5 modulators would be more specific and have less of the potential adverse effects of other glutamates. Most drugs that we think of affecting glutamate, like amantadine and memantine (used for Alzheimer's disease), have some NMDA antagonist effect, but this is relatively mild. 

David Charles, MD, and Thomas Davis, MD, of the Vanderbilt University Department of Neurology, recently spoke with Neurology Reviews about the treatment pipeline and latest research in levodopa-induced dyskinesia in Parkinson's disease.

How is the treatment pipeline advancing for different types of levodopa-induced dyskinesia (LID)?
 
Dr. Thomas Davis: Dyskinesia has traditionally been hard to quantify, and we have been lacking any US Food and Drug Administration (FDA)-approved anti-dyskinesia drugs. The pipeline has historically been strongest for wearing-off because it is easier to measure on time than to quantify involuntary movements.

The Unified Dyskinesia Rating Scale (UDysRS), released in 2008 by the Movement Disorder Society, provided a standardized scale that allowed dyskinesia clinical trials to move forward. The UDysRS was used as the primary outcome for the extended release amantadine capsule study. This was important because it demonstrated the possibility of a successful clinical trial design to get a drug approved for dyskinesia, which will encourage others to test more potential new treatments.
 
What is the status of research on deep brain stimulation (DBS) for Parkinson's disease, and when might it be considered?
 
Dr. David Charles: This is one of the areas of research that we're focused on here at Vanderbilt. All 3 of the FDA-approved device manufacturers have been conducting research in technology refinement and improvements. These advances include not only patient programmers and physician programmers, but also new sensing capability and lead designs. Some of the manufacturers now have leads that allow the physician to steer the current in one direction or another, where traditionally the current has been delivered in a circumferential contact that's shaped like a cylinder, where the energy is transmitted 360 degrees from the lead. The new designs allow you to steer the current hopefully toward areas that provide more efficacy and away from areas that cause side effects. Even more exciting is the emerging sensing capability that may allow the development of stimulating technology that is responsive to fluctuating symptoms. There is keen research interest in understanding whether a device could detect a specific neuronal firing pattern and then respond with an individually tailored stimulation to improve symptoms as needed. Will the next generation of deep brain stimulating devices detect the pattern and deliver energy in a more targeted and precise way, responsive to what it's sensing from the patient's brain? I think that's an area of research that's really exciting.
 
In regard to when it might be considered: The ability to steer the current is already available in 2 of the 3 systems that are on the market today. Having current that is steerable in all 3 will be coming in the not too distant future. The available devices already have improved programming platforms for health care providers as well.
 
Our research at Vanderbilt is focused on DBS in early-stage Parkinson's disease. There is a paper published in Neurology that reports Class II evidencet hat DBS applied in early-stage Parkinson's disease slows the progression of tremor. This is exciting because none of the available treatments change the progression of disease—they're currently accepted as symptomatic therapies only. In this publication, we report that participants receiving DBS in the very earliest stages of Parkinson's disease it may slow the progression of rest tremor. We now have approval from the FDA to conduct a large-scale phase 3, multicenter, clinical trial of DBS in early-stage Parkinson's disease, with the primary endpoint focused on slowing progression of tremor, a cardinal feature of the disease. This upcoming trial is approved by the FDA as a pivotal trial, meaning that the findings could potentially be used to change the labeling of DBS devices. Our goal is to obtain Class I evidence of slowing the progression of tremor or other elements of the disease.
 
Dr. Thomas Davis: If you are a device manufacturer for DBS it is natural for you to aim to make better devices, better batteries, better programming, and better electrodes than your competitor. That's really where the industry-based research is right now. Clinicians are still determining which device is the best candidate, where the best target in the brain is, and when to use DBS.

When would a health care practitioner decide to try frequent smaller dosages or immediate-release formulations of dopaminergic drugs to control levodopa-induced dyskinesia (LID), compared with non-dopaminergic treatments that are available? What are some pros and cons of each approach?
 
Dr. David Charles: If you have a patient who's already on levodopa, it's not uncommon that—separate from the way we prescribe the medicine—the patients experiment with their medicine to some degree. At the very least, people occasionally forget to take a dose and they feel the effect of a missed dose. They may take an extra dose or an extra half dose, particularly if they feel that the last dose isn't working as well, or in the event they have some special occasion coming up. 
 
Over time, patients and physicians learn that sometimes smaller, more frequent dosing of levodopa can be a helpful strategy for certain individuals. One advantage is that it's the medication that the patient is already taking, and they're just simply breaking tablets. Many pharmacies will break tablets for patients so they can take some smaller doses more frequently. Obviously, there can be downsides to that, such as it becoming harder to remember to take more frequent doses.
 
Dr. Thomas Davis: I would agree that the biggest advantage of taking more frequent, smaller doses is that it's cheaper than adding an adjunct or moving to a more invasive therapy.  More frequent smaller doses of levodopa also generally has no side effects because if you're taking 2 carbidopa/levodopa 3 times a day and you're tolerating it, but you're having peak dose problems, you can then switch to 1.5 tablets 4 times a day. It involves more work and planning, but it's no more total medication than the patient is taking already, so this strategy usually does not have any unexpected side effects. It really boils down to how much work the patient wants to put in, how adherent they are to medication dosing, and whether they want to add another medication.
 
Most of the adjunctive medications to treat motor fluctuations are approved to improve on-time in Parkinson's disease patients with wearing off. These include the monoamine oxidase inhibitors, COMT inhibitors, and adenosine A2A antagonists. For treatment of dyskinesia, only the extended release capsule formulation of amantadine has FDA approval, although all formulations are approved for Parkinson's disease and are used clinically to dampen dyskinesia. How long to try these strategies before moving to one of the more advanced therapies, like DBS or jejunal infusion of levodopa, is not clear. It's great to have options, but it makes the decisions a lot harder.
 
Dr. David Charles: Dr. Davis raised the question of what medicine to choose, and what's your next choice in a patient who's having wearing-off dyskinesia or LID and so forth. There is an increasing number of options for those mid-stage patients. The pitfall is feeling that you have to try every available medication and combination before moving to a more advanced therapy.  The physician risks churning through the various combinations for so long that the benefit of an advanced therapy becomes shortened or lost altogether. 
 
Take epilepsy, for example. In operative candidates, surgery is often more beneficial when applied earlier. There's solid data to support that adding on multiple anti-epileptics medications is not always helpful. Continuing to add or change medications can actually diminish returns, particularly in a person who could receive benefit from surgery for epilepsy. 
 
I get the sense that the same may be true for dyskinesia. In clinical practice, we often receive DBS referrals when a patient's community-based physician has tried various medications and combination therapies until the point that the patient and the physician have become totally frustrated. By the time they are referred, the patient may benefit from DBS, but not nearly as well and as for long as they could have if they had received it earlier. We as physicians have to be mindful that while we have these increasing number of options—which is a good thing for both patients and physicians—that we don't continue to use them to the point that it takes away the option of more advanced therapies for appropriate candidates.
 
Metabotropic glutamate (mGlu) receptors have been receiving attention as potential therapeutic targets for LID. How do these compare with other receptors such as N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA)?
 
Dr. Thomas Davis: NMDA and AMPA are traditional ionotropic receptors, meaning that they are ligand gated, that they are almost exclusively excitatory, and that they generally have to do with the flow of potassium. 
 
mGlu receptors are protein coupled receptors. They have more elaborate action and may be either excitatory or inhibitory. Though mGlu, NMDA, and AMPA are completely different, they are all activated by glutamate. Pharmacologically utilizing the mGlu receptors is a relatively new and novel idea. Specifically, mGlu-5 receptors have received the most attention as potentially having an anti-parkinsonian effect and possibly dampening dyskinesia. The mGlu-5 receptors are an attractive target because they are concentrated in the striatum, as opposed to other glutamatergic receptors that are more diffusely located. It was felt that mGlu-5 modulators would be more specific and have less of the potential adverse effects of other glutamates. Most drugs that we think of affecting glutamate, like amantadine and memantine (used for Alzheimer's disease), have some NMDA antagonist effect, but this is relatively mild. 

Differences in metabolism of levodopa between patients with Parkinson’s disease may be caused by variations in gut bacteria, according to investigators.

Specifically, patients with a higher abundance of Enterococcus faecalis may be converting levodopa into dopamine via decarboxylation before it can cross the blood-brain barrier, reported Emily P. Balskus, PhD, of Harvard University in Cambridge, Mass.

Although existing decarboxylase inhibitors, such as carbidopa, can reduce metabolism of levodopa by host enzymes, these drugs are unable to inhibit the enzymatic activity of E. faecalis in the gut, Dr. Balskus said at the annual Gut Microbiota for Health World Summit, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility.

“[Carbidopa] is actually completely ineffective at inhibiting decarboxylation in human fecal suspension,” Dr. Balskus said, referring to research led by PhD student Vayu Maini Rekdal. “We think that this could indicate that patients who are taking carbidopa are not inhibiting any bacterial metabolism that they may have.”

While previous research showed that E. faecalis could decarboxylate levodopa, Dr. Balskus and colleagues linked this process with the tyrosine decarboxylase gene (TyrDC), and showed that the of abundance E. faecalis and TyrDC correlate with levodopa metabolism.

Unlike the human enzyme responsible for decarboxylation of levodopa, the E. faecalis enzyme preferentially binds with L-tyrosine. This could explain why existing decarboxylase inhibitors have little impact on decarboxylation in the gut, Dr. Balskus said.

She also noted that this unique characteristic may open doors to new therapeutics. In the lab, Dr. Balskus and colleagues tested a decarboxylase inhibitor that resembled L-tyrosine, (S)-alpha-fluoromethyltyrosine (AFMT). Indeed, AFMT completely inhibited of decarboxylation of levodopa in both E. faecalis cells and complex human microbiome samples.

“We think this is pretty exciting,” Dr. Balskus said.

Early animal studies support this enthusiasm, as germ-free mice colonized with E. faecalis maintain higher serum levels of levodopa with concurrent administration of AFMT.

“We think that this could indicate that a promising way to improve levodopa therapy for Parkinson’s patients would be to develop compounds that inhibit bacterial drug metabolism activity,” Dr. Balskus said.

Concluding her presentation, Dr. Balskus emphasized the importance of a biochemical approach to microbiome research. “Studying enzymes opens up new, exciting opportunities for microbiome manipulation. We can design or develop inhibitors of enzymes, use those inhibitors as tools to study the roles of individual metabolic activities, and potentially use them as therapeutics. We are very excited about the possibility of treating or preventing human disease not just by manipulating processes in our own cells, but by targeting activities in the microbiota.”

Dr. Balskus reported funding from HHMI, the Bill and Melinda Gates Foundation, the David and Lucile Packard Foundation, and Merck.

Differences in metabolism of levodopa between patients with Parkinson’s disease may be caused by variations in gut bacteria, according to investigators.

Specifically, patients with a higher abundance of Enterococcus faecalis may be converting levodopa into dopamine via decarboxylation before it can cross the blood-brain barrier, reported Emily P. Balskus, PhD, of Harvard University in Cambridge, Mass.

Although existing decarboxylase inhibitors, such as carbidopa, can reduce metabolism of levodopa by host enzymes, these drugs are unable to inhibit the enzymatic activity of E. faecalis in the gut, Dr. Balskus said at the annual Gut Microbiota for Health World Summit, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility.

“[Carbidopa] is actually completely ineffective at inhibiting decarboxylation in human fecal suspension,” Dr. Balskus said, referring to research led by PhD student Vayu Maini Rekdal. “We think that this could indicate that patients who are taking carbidopa are not inhibiting any bacterial metabolism that they may have.”

While previous research showed that E. faecalis could decarboxylate levodopa, Dr. Balskus and colleagues linked this process with the tyrosine decarboxylase gene (TyrDC), and showed that the of abundance E. faecalis and TyrDC correlate with levodopa metabolism.

Unlike the human enzyme responsible for decarboxylation of levodopa, the E. faecalis enzyme preferentially binds with L-tyrosine. This could explain why existing decarboxylase inhibitors have little impact on decarboxylation in the gut, Dr. Balskus said.

She also noted that this unique characteristic may open doors to new therapeutics. In the lab, Dr. Balskus and colleagues tested a decarboxylase inhibitor that resembled L-tyrosine, (S)-alpha-fluoromethyltyrosine (AFMT). Indeed, AFMT completely inhibited of decarboxylation of levodopa in both E. faecalis cells and complex human microbiome samples.

“We think this is pretty exciting,” Dr. Balskus said.

Early animal studies support this enthusiasm, as germ-free mice colonized with E. faecalis maintain higher serum levels of levodopa with concurrent administration of AFMT.

“We think that this could indicate that a promising way to improve levodopa therapy for Parkinson’s patients would be to develop compounds that inhibit bacterial drug metabolism activity,” Dr. Balskus said.

Concluding her presentation, Dr. Balskus emphasized the importance of a biochemical approach to microbiome research. “Studying enzymes opens up new, exciting opportunities for microbiome manipulation. We can design or develop inhibitors of enzymes, use those inhibitors as tools to study the roles of individual metabolic activities, and potentially use them as therapeutics. We are very excited about the possibility of treating or preventing human disease not just by manipulating processes in our own cells, but by targeting activities in the microbiota.”

Dr. Balskus reported funding from HHMI, the Bill and Melinda Gates Foundation, the David and Lucile Packard Foundation, and Merck.

Differences in metabolism of levodopa between patients with Parkinson’s disease may be caused by variations in gut bacteria, according to investigators.

Specifically, patients with a higher abundance of Enterococcus faecalis may be converting levodopa into dopamine via decarboxylation before it can cross the blood-brain barrier, reported Emily P. Balskus, PhD, of Harvard University in Cambridge, Mass.

Although existing decarboxylase inhibitors, such as carbidopa, can reduce metabolism of levodopa by host enzymes, these drugs are unable to inhibit the enzymatic activity of E. faecalis in the gut, Dr. Balskus said at the annual Gut Microbiota for Health World Summit, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility.

“[Carbidopa] is actually completely ineffective at inhibiting decarboxylation in human fecal suspension,” Dr. Balskus said, referring to research led by PhD student Vayu Maini Rekdal. “We think that this could indicate that patients who are taking carbidopa are not inhibiting any bacterial metabolism that they may have.”

While previous research showed that E. faecalis could decarboxylate levodopa, Dr. Balskus and colleagues linked this process with the tyrosine decarboxylase gene (TyrDC), and showed that the of abundance E. faecalis and TyrDC correlate with levodopa metabolism.

Unlike the human enzyme responsible for decarboxylation of levodopa, the E. faecalis enzyme preferentially binds with L-tyrosine. This could explain why existing decarboxylase inhibitors have little impact on decarboxylation in the gut, Dr. Balskus said.

She also noted that this unique characteristic may open doors to new therapeutics. In the lab, Dr. Balskus and colleagues tested a decarboxylase inhibitor that resembled L-tyrosine, (S)-alpha-fluoromethyltyrosine (AFMT). Indeed, AFMT completely inhibited of decarboxylation of levodopa in both E. faecalis cells and complex human microbiome samples.

“We think this is pretty exciting,” Dr. Balskus said.

Early animal studies support this enthusiasm, as germ-free mice colonized with E. faecalis maintain higher serum levels of levodopa with concurrent administration of AFMT.

“We think that this could indicate that a promising way to improve levodopa therapy for Parkinson’s patients would be to develop compounds that inhibit bacterial drug metabolism activity,” Dr. Balskus said.

Concluding her presentation, Dr. Balskus emphasized the importance of a biochemical approach to microbiome research. “Studying enzymes opens up new, exciting opportunities for microbiome manipulation. We can design or develop inhibitors of enzymes, use those inhibitors as tools to study the roles of individual metabolic activities, and potentially use them as therapeutics. We are very excited about the possibility of treating or preventing human disease not just by manipulating processes in our own cells, but by targeting activities in the microbiota.”

Dr. Balskus reported funding from HHMI, the Bill and Melinda Gates Foundation, the David and Lucile Packard Foundation, and Merck.

Eye and vision problems are highly prevalent among patients with Parkinson’s disease and often severe enough to interfere with daily activities, according to the results of a multicenter, cross-sectional cohort study.

“Ophthalmologic symptoms are underreported by patients with Parkinson’s disease and often overlooked by their treating physicians,” noted the investigators, who were led by Carlijn D.J.M. Borm, MD, Parkinson Centre Nijmegen (the Netherlands), Department of Neurology, Donders Institute for Brain, Cognition and Behaviour at Radboud University Medical Centre. “Importantly, intact vision is especially vital for patients with Parkinson’s disease to compensate (through visual guidance) for their common loss of motor automaticity that is caused by basal ganglia dysfunction.”

The investigators studied 848 patients with Parkinson’s disease in the Netherlands and Austria who were recruited by e-mail or in outpatient clinics and 250 age-matched healthy controls drawn from partners and acquaintances, comparing the groups on symptoms assessed with the Visual Impairment in Parkinson’s Disease Questionnaire (VIPD-Q).

Results reported in Neurology showed that 82% of patients with Parkinson’s disease reported at least one ophthalmologic symptom, compared with 48% of age-matched healthy controls (P < .001). Symptoms related to the ocular surface – blurry near vision, a burning or gritty sensation, mucus or particles, and watering of the eyes – were the most common.

Moreover, 68% of patients reported having ophthalmologic symptoms that interfered with daily activities, compared with 35% of healthy controls (P < .001).

The study’s findings suggest “that either Parkinson’s disease itself or its treatment has an effect on ophthalmologic functions beyond the normal aging process,” Dr. Borm and coinvestigators wrote. “The high prevalence of ophthalmologic symptoms and their effect on daily life is striking, and emphasizes the need to address this subject in both research and clinical practice.”

“Patients who report ophthalmologic symptoms need a referral for further evaluation. For those patients who do not volunteer problems themselves, a screening questionnaire such as the VIPD-Q may help with identifying ophthalmologic symptoms in patients with Parkinson’s disease that might otherwise be missed, thereby enabling timely referral and treatment,” they noted.
 

Study details

The study participants were 70 years old, on average, and the patients with Parkinson’s disease had had the disease for a median duration of 7 years. Compared with the healthy control group, the patient group more often reported that they used visual aids (95% vs. 88%; P = .001) and had visited an ophthalmologist (35% vs. 19%; P < .001). The median score on the VIPD-Q, out of a possible 51 points, was 10 among the patients with Parkinson’s disease, compared with 2 among the healthy controls (P < .001).

Patients most commonly reported symptoms related to the ocular surface (63% vs. 24% among controls; P < .001). But they also often reported symptoms in the intraocular domain (54% vs. 25%; P < .001), the oculomotor domain (44% vs. 10%; P < .001), and the optic nerve domain (44% vs. 19%; P < .001). Fully 22% of the patients reported visual hallucinations, compared with just 2% of the healthy controls (P < .001).

As VIPD-Q score increased, so did the likelihood of falls (odds ratio, 1.043; P < .001). In addition, patients with Parkinson’s disease more often reported that ophthalmologic symptoms had a moderate or severe impact on their quality of life (53% vs. 16%; P < .001).

Dr. Borm disclosed no relevant conflicts of interest. The study was funded by the Stichting Parkinson Fonds.
 

Awareness is key to spotting these treatable symptoms

“This study confirms a lot of what we already knew about Parkinson’s disease, but it gives more numbers to it and also the patient’s perspective rather than the doctor’s perspective,” Andrew G. Lee, MD, commented in an interview. “We know that patients with Parkinson’s disease have a lot of ophthalmologic symptoms – probably more than we recognize or ask about in the clinic – and their symptoms predominantly are out of proportion to what we see on exam,” said Dr. Lee, who is chairman of the Department of Ophthalmology at Blanton Eye Institute, Houston Methodist Hospital.

In fact, patients may have normal acuity, normal visual fields, and a normal structural eye exam, yet still report vision problems because of the central neurodegeneration occurring, he noted. “Ophthalmologists cannot rely on just the eye exam when examining patients with Parkinson’s disease. They have to take symptoms into consideration. It’s really important to be aware of how brain disease can affect the eyes symptom-wise, even though the eye exam is normal.”

Administering the questionnaire used in the study is not very difficult but is somewhat time consuming, so most ophthalmologists and neurologists are unlikely to use it, according to Dr. Lee. But knowing common symptoms and asking about them can ensure they are promptly recognized, the first step in addressing them.

“None of the visual complaints in patients with Parkinson’s disease are curable because Parkinson’s disease is not curable and the disease is the underlying major etiology for the problems. However, all of the symptoms have treatments,” he said.

For example, dry eye, caused by decreased blinking, can be treated with drops. Convergence insufficiency, which generates double vision when focusing on nearby objects, can be managed with prisms, exercises, and if needed, eye muscle surgery. Impaired eye movement is best treated with different sets of glasses specific to tasks, such as one pair for reading and one pair for distance. And visual hallucinations can be addressed with changes to existing medications or new medication, or simple reassurance that the hallucinations aren’t harmful.

“It’s important that this kind of study increases awareness in the medical community,” concluded Dr. Lee, who disclosed no relevant conflicts of interest. “The take-home messages are that eye doctors know that these are real complaints, that the eye exam is not going to give the answer, and that all of the symptoms have treatments even though there is no cure.”

SOURCE: Borm CDJM et al. Neurology. 2020 Mar 11. doi: 10.1212/WNL.0000000000009214.

Eye and vision problems are highly prevalent among patients with Parkinson’s disease and often severe enough to interfere with daily activities, according to the results of a multicenter, cross-sectional cohort study.

“Ophthalmologic symptoms are underreported by patients with Parkinson’s disease and often overlooked by their treating physicians,” noted the investigators, who were led by Carlijn D.J.M. Borm, MD, Parkinson Centre Nijmegen (the Netherlands), Department of Neurology, Donders Institute for Brain, Cognition and Behaviour at Radboud University Medical Centre. “Importantly, intact vision is especially vital for patients with Parkinson’s disease to compensate (through visual guidance) for their common loss of motor automaticity that is caused by basal ganglia dysfunction.”

The investigators studied 848 patients with Parkinson’s disease in the Netherlands and Austria who were recruited by e-mail or in outpatient clinics and 250 age-matched healthy controls drawn from partners and acquaintances, comparing the groups on symptoms assessed with the Visual Impairment in Parkinson’s Disease Questionnaire (VIPD-Q).

Results reported in Neurology showed that 82% of patients with Parkinson’s disease reported at least one ophthalmologic symptom, compared with 48% of age-matched healthy controls (P < .001). Symptoms related to the ocular surface – blurry near vision, a burning or gritty sensation, mucus or particles, and watering of the eyes – were the most common.

Moreover, 68% of patients reported having ophthalmologic symptoms that interfered with daily activities, compared with 35% of healthy controls (P < .001).

The study’s findings suggest “that either Parkinson’s disease itself or its treatment has an effect on ophthalmologic functions beyond the normal aging process,” Dr. Borm and coinvestigators wrote. “The high prevalence of ophthalmologic symptoms and their effect on daily life is striking, and emphasizes the need to address this subject in both research and clinical practice.”

“Patients who report ophthalmologic symptoms need a referral for further evaluation. For those patients who do not volunteer problems themselves, a screening questionnaire such as the VIPD-Q may help with identifying ophthalmologic symptoms in patients with Parkinson’s disease that might otherwise be missed, thereby enabling timely referral and treatment,” they noted.
 

Study details

The study participants were 70 years old, on average, and the patients with Parkinson’s disease had had the disease for a median duration of 7 years. Compared with the healthy control group, the patient group more often reported that they used visual aids (95% vs. 88%; P = .001) and had visited an ophthalmologist (35% vs. 19%; P < .001). The median score on the VIPD-Q, out of a possible 51 points, was 10 among the patients with Parkinson’s disease, compared with 2 among the healthy controls (P < .001).

Patients most commonly reported symptoms related to the ocular surface (63% vs. 24% among controls; P < .001). But they also often reported symptoms in the intraocular domain (54% vs. 25%; P < .001), the oculomotor domain (44% vs. 10%; P < .001), and the optic nerve domain (44% vs. 19%; P < .001). Fully 22% of the patients reported visual hallucinations, compared with just 2% of the healthy controls (P < .001).

As VIPD-Q score increased, so did the likelihood of falls (odds ratio, 1.043; P < .001). In addition, patients with Parkinson’s disease more often reported that ophthalmologic symptoms had a moderate or severe impact on their quality of life (53% vs. 16%; P < .001).

Dr. Borm disclosed no relevant conflicts of interest. The study was funded by the Stichting Parkinson Fonds.
 

Awareness is key to spotting these treatable symptoms

“This study confirms a lot of what we already knew about Parkinson’s disease, but it gives more numbers to it and also the patient’s perspective rather than the doctor’s perspective,” Andrew G. Lee, MD, commented in an interview. “We know that patients with Parkinson’s disease have a lot of ophthalmologic symptoms – probably more than we recognize or ask about in the clinic – and their symptoms predominantly are out of proportion to what we see on exam,” said Dr. Lee, who is chairman of the Department of Ophthalmology at Blanton Eye Institute, Houston Methodist Hospital.

In fact, patients may have normal acuity, normal visual fields, and a normal structural eye exam, yet still report vision problems because of the central neurodegeneration occurring, he noted. “Ophthalmologists cannot rely on just the eye exam when examining patients with Parkinson’s disease. They have to take symptoms into consideration. It’s really important to be aware of how brain disease can affect the eyes symptom-wise, even though the eye exam is normal.”

Administering the questionnaire used in the study is not very difficult but is somewhat time consuming, so most ophthalmologists and neurologists are unlikely to use it, according to Dr. Lee. But knowing common symptoms and asking about them can ensure they are promptly recognized, the first step in addressing them.

“None of the visual complaints in patients with Parkinson’s disease are curable because Parkinson’s disease is not curable and the disease is the underlying major etiology for the problems. However, all of the symptoms have treatments,” he said.

For example, dry eye, caused by decreased blinking, can be treated with drops. Convergence insufficiency, which generates double vision when focusing on nearby objects, can be managed with prisms, exercises, and if needed, eye muscle surgery. Impaired eye movement is best treated with different sets of glasses specific to tasks, such as one pair for reading and one pair for distance. And visual hallucinations can be addressed with changes to existing medications or new medication, or simple reassurance that the hallucinations aren’t harmful.

“It’s important that this kind of study increases awareness in the medical community,” concluded Dr. Lee, who disclosed no relevant conflicts of interest. “The take-home messages are that eye doctors know that these are real complaints, that the eye exam is not going to give the answer, and that all of the symptoms have treatments even though there is no cure.”

SOURCE: Borm CDJM et al. Neurology. 2020 Mar 11. doi: 10.1212/WNL.0000000000009214.

Eye and vision problems are highly prevalent among patients with Parkinson’s disease and often severe enough to interfere with daily activities, according to the results of a multicenter, cross-sectional cohort study.

“Ophthalmologic symptoms are underreported by patients with Parkinson’s disease and often overlooked by their treating physicians,” noted the investigators, who were led by Carlijn D.J.M. Borm, MD, Parkinson Centre Nijmegen (the Netherlands), Department of Neurology, Donders Institute for Brain, Cognition and Behaviour at Radboud University Medical Centre. “Importantly, intact vision is especially vital for patients with Parkinson’s disease to compensate (through visual guidance) for their common loss of motor automaticity that is caused by basal ganglia dysfunction.”

The investigators studied 848 patients with Parkinson’s disease in the Netherlands and Austria who were recruited by e-mail or in outpatient clinics and 250 age-matched healthy controls drawn from partners and acquaintances, comparing the groups on symptoms assessed with the Visual Impairment in Parkinson’s Disease Questionnaire (VIPD-Q).

Results reported in Neurology showed that 82% of patients with Parkinson’s disease reported at least one ophthalmologic symptom, compared with 48% of age-matched healthy controls (P < .001). Symptoms related to the ocular surface – blurry near vision, a burning or gritty sensation, mucus or particles, and watering of the eyes – were the most common.

Moreover, 68% of patients reported having ophthalmologic symptoms that interfered with daily activities, compared with 35% of healthy controls (P < .001).

The study’s findings suggest “that either Parkinson’s disease itself or its treatment has an effect on ophthalmologic functions beyond the normal aging process,” Dr. Borm and coinvestigators wrote. “The high prevalence of ophthalmologic symptoms and their effect on daily life is striking, and emphasizes the need to address this subject in both research and clinical practice.”

“Patients who report ophthalmologic symptoms need a referral for further evaluation. For those patients who do not volunteer problems themselves, a screening questionnaire such as the VIPD-Q may help with identifying ophthalmologic symptoms in patients with Parkinson’s disease that might otherwise be missed, thereby enabling timely referral and treatment,” they noted.
 

Study details

The study participants were 70 years old, on average, and the patients with Parkinson’s disease had had the disease for a median duration of 7 years. Compared with the healthy control group, the patient group more often reported that they used visual aids (95% vs. 88%; P = .001) and had visited an ophthalmologist (35% vs. 19%; P < .001). The median score on the VIPD-Q, out of a possible 51 points, was 10 among the patients with Parkinson’s disease, compared with 2 among the healthy controls (P < .001).

Patients most commonly reported symptoms related to the ocular surface (63% vs. 24% among controls; P < .001). But they also often reported symptoms in the intraocular domain (54% vs. 25%; P < .001), the oculomotor domain (44% vs. 10%; P < .001), and the optic nerve domain (44% vs. 19%; P < .001). Fully 22% of the patients reported visual hallucinations, compared with just 2% of the healthy controls (P < .001).

As VIPD-Q score increased, so did the likelihood of falls (odds ratio, 1.043; P < .001). In addition, patients with Parkinson’s disease more often reported that ophthalmologic symptoms had a moderate or severe impact on their quality of life (53% vs. 16%; P < .001).

Dr. Borm disclosed no relevant conflicts of interest. The study was funded by the Stichting Parkinson Fonds.
 

Awareness is key to spotting these treatable symptoms

“This study confirms a lot of what we already knew about Parkinson’s disease, but it gives more numbers to it and also the patient’s perspective rather than the doctor’s perspective,” Andrew G. Lee, MD, commented in an interview. “We know that patients with Parkinson’s disease have a lot of ophthalmologic symptoms – probably more than we recognize or ask about in the clinic – and their symptoms predominantly are out of proportion to what we see on exam,” said Dr. Lee, who is chairman of the Department of Ophthalmology at Blanton Eye Institute, Houston Methodist Hospital.

In fact, patients may have normal acuity, normal visual fields, and a normal structural eye exam, yet still report vision problems because of the central neurodegeneration occurring, he noted. “Ophthalmologists cannot rely on just the eye exam when examining patients with Parkinson’s disease. They have to take symptoms into consideration. It’s really important to be aware of how brain disease can affect the eyes symptom-wise, even though the eye exam is normal.”

Administering the questionnaire used in the study is not very difficult but is somewhat time consuming, so most ophthalmologists and neurologists are unlikely to use it, according to Dr. Lee. But knowing common symptoms and asking about them can ensure they are promptly recognized, the first step in addressing them.

“None of the visual complaints in patients with Parkinson’s disease are curable because Parkinson’s disease is not curable and the disease is the underlying major etiology for the problems. However, all of the symptoms have treatments,” he said.

For example, dry eye, caused by decreased blinking, can be treated with drops. Convergence insufficiency, which generates double vision when focusing on nearby objects, can be managed with prisms, exercises, and if needed, eye muscle surgery. Impaired eye movement is best treated with different sets of glasses specific to tasks, such as one pair for reading and one pair for distance. And visual hallucinations can be addressed with changes to existing medications or new medication, or simple reassurance that the hallucinations aren’t harmful.

“It’s important that this kind of study increases awareness in the medical community,” concluded Dr. Lee, who disclosed no relevant conflicts of interest. “The take-home messages are that eye doctors know that these are real complaints, that the eye exam is not going to give the answer, and that all of the symptoms have treatments even though there is no cure.”

SOURCE: Borm CDJM et al. Neurology. 2020 Mar 11. doi: 10.1212/WNL.0000000000009214.

A growing body of research links the gut with the brain and behavior, but compartmentalization within the medical community may be slowing investigation of the gut-brain axis, according to a leading expert.

Studies have shown that the microbiome may influence a diverse range of behavioral and neurological processes, from acute and chronic stress responses to development of Parkinson’s and Alzheimer’s disease, reported John F. Cryan, PhD, of University College Cork, Ireland.

Dr. Cryan began his presentation at the annual Gut Microbiota for Health World Summit by citing Hippocrates, who is thought to have stated that all diseases begin in the gut.

“That can be quite strange when I talk to my neurology or psychiatry colleagues,” Dr. Cryan said. “They sometimes look at me like I have two heads. Because in medicine we compartmentalize, and if you are studying neurology or psychiatry or [you are] in clinical practice, you are focusing on everything from the neck upwards.”

For more than a decade, Dr. Cryan and colleagues have been investigating the gut-brain axis, predominantly in mouse models, but also across animal species and in humans.

At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Cryan reviewed a variety of representative studies.

For instance, in both mice and humans, research has shown that C-section, which is associated with poorer microbiome diversity than vaginal delivery, has also been linked with social deficits and elevated stress responses. And in the case of mice, coprophagia, in which cesarean-delivered mice eat the feces of vaginally born mice, has been shown to ameliorate these psychiatric effects.

Dr. Cryan likened this process to an “artificial fecal transplant.”

“You know, co-housing and eating each other’s poo is not the translational approach that we were advocating by any means,” Dr. Cryan said. “But at least it tells us – in a proof-of-concept way – that if we change the microbiome, then we can reverse what’s going on.”

While the mechanisms behind the gut-brain axis remain incompletely understood, Dr. Cryan noted that the vagus nerve, which travels from the gut to the brain, plays a central role, and that transecting this nerve in mice stops the microbiome from affecting the brain.

“What happens in vagus doesn’t just stay in vagus, but will actually affect our emotions in different ways,” Dr. Cryan said.

He emphasized that communication travels both ways along the gut-brain axis, and went on to describe how this phenomenon has been demonstrated across a wide array of animals.

“From insects all the way through to primates, if you start to interfere with social behavior, you change the microbiome,” Dr. Cryan said. “But the opposite is also true; if you start to change the microbiome you can start to have widespread effects on social behavior.”

In humans, manipulating the microbiome could open up new psychiatric frontiers, Dr. Cryan said.

“[In the past 30 years], there really have been no real advances in how we manage mental health,” he said. “That’s very sobering when we are having such a mental health problem across all ages right now. And so perhaps it’s time for what we’ve coined the ‘psychobiotic revolution’ – time for a new way of thinking about mental health.”

According to Dr. Cryan, psychobiotics are interventions that target the microbiome for mental health purposes, including fermented foods, probiotics, prebiotics, synbiotics, parabiotics, and postbiotics.

Among these, probiotics have been a focal point of interventional research. Although results have been mixed, Dr. Cryan suggested that negative probiotic studies are more likely due to bacterial strain than a failure of the concept as a whole.

“Most strains of bacteria will do absolutely nothing,” Dr. Cryan said. “Strain is really important.”

In demonstration of this concept, he recounted a 2017 study conducted at University College Cork in which 22 healthy volunteers were given Bifidobacterium longum 1714, and then subjected to a social stress test. The results, published in Translational Psychiatry, showed that the probiotic, compared with placebo, was associated with attenuated stress responses, reduced daily stress, and enhanced visuospatial memory.

In contrast, a similar study by Dr. Cryan and colleagues, which tested Lactobacillus rhamnosus (JB-1), fell short.

“You [could not have gotten] more negative data into one paper if you tried,” Dr. Cryan said, referring to the study. “It did absolutely nothing.”

To find out which psychobiotics may have an impact, and how, Dr. Cryan called for more research.

“It’s still early days,” he said. “We probably have more meta-analyses and systematic reviews of the field than we have primary research papers.

Dr. Cryan concluded his presentation on an optimistic note.

“Neurology is waking up ... to understand that the microbiome could be playing a key role in many, many other disorders. ... Overall, what we’re beginning to see is that our state of gut markedly affects our state of mind.”

Dr. Cryan disclosed relationships with Abbott Nutrition, Roche Pharma, Nutricia, and others.

A growing body of research links the gut with the brain and behavior, but compartmentalization within the medical community may be slowing investigation of the gut-brain axis, according to a leading expert.

Studies have shown that the microbiome may influence a diverse range of behavioral and neurological processes, from acute and chronic stress responses to development of Parkinson’s and Alzheimer’s disease, reported John F. Cryan, PhD, of University College Cork, Ireland.

Dr. Cryan began his presentation at the annual Gut Microbiota for Health World Summit by citing Hippocrates, who is thought to have stated that all diseases begin in the gut.

“That can be quite strange when I talk to my neurology or psychiatry colleagues,” Dr. Cryan said. “They sometimes look at me like I have two heads. Because in medicine we compartmentalize, and if you are studying neurology or psychiatry or [you are] in clinical practice, you are focusing on everything from the neck upwards.”

For more than a decade, Dr. Cryan and colleagues have been investigating the gut-brain axis, predominantly in mouse models, but also across animal species and in humans.

At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Cryan reviewed a variety of representative studies.

For instance, in both mice and humans, research has shown that C-section, which is associated with poorer microbiome diversity than vaginal delivery, has also been linked with social deficits and elevated stress responses. And in the case of mice, coprophagia, in which cesarean-delivered mice eat the feces of vaginally born mice, has been shown to ameliorate these psychiatric effects.

Dr. Cryan likened this process to an “artificial fecal transplant.”

“You know, co-housing and eating each other’s poo is not the translational approach that we were advocating by any means,” Dr. Cryan said. “But at least it tells us – in a proof-of-concept way – that if we change the microbiome, then we can reverse what’s going on.”

While the mechanisms behind the gut-brain axis remain incompletely understood, Dr. Cryan noted that the vagus nerve, which travels from the gut to the brain, plays a central role, and that transecting this nerve in mice stops the microbiome from affecting the brain.

“What happens in vagus doesn’t just stay in vagus, but will actually affect our emotions in different ways,” Dr. Cryan said.

He emphasized that communication travels both ways along the gut-brain axis, and went on to describe how this phenomenon has been demonstrated across a wide array of animals.

“From insects all the way through to primates, if you start to interfere with social behavior, you change the microbiome,” Dr. Cryan said. “But the opposite is also true; if you start to change the microbiome you can start to have widespread effects on social behavior.”

In humans, manipulating the microbiome could open up new psychiatric frontiers, Dr. Cryan said.

“[In the past 30 years], there really have been no real advances in how we manage mental health,” he said. “That’s very sobering when we are having such a mental health problem across all ages right now. And so perhaps it’s time for what we’ve coined the ‘psychobiotic revolution’ – time for a new way of thinking about mental health.”

According to Dr. Cryan, psychobiotics are interventions that target the microbiome for mental health purposes, including fermented foods, probiotics, prebiotics, synbiotics, parabiotics, and postbiotics.

Among these, probiotics have been a focal point of interventional research. Although results have been mixed, Dr. Cryan suggested that negative probiotic studies are more likely due to bacterial strain than a failure of the concept as a whole.

“Most strains of bacteria will do absolutely nothing,” Dr. Cryan said. “Strain is really important.”

In demonstration of this concept, he recounted a 2017 study conducted at University College Cork in which 22 healthy volunteers were given Bifidobacterium longum 1714, and then subjected to a social stress test. The results, published in Translational Psychiatry, showed that the probiotic, compared with placebo, was associated with attenuated stress responses, reduced daily stress, and enhanced visuospatial memory.

In contrast, a similar study by Dr. Cryan and colleagues, which tested Lactobacillus rhamnosus (JB-1), fell short.

“You [could not have gotten] more negative data into one paper if you tried,” Dr. Cryan said, referring to the study. “It did absolutely nothing.”

To find out which psychobiotics may have an impact, and how, Dr. Cryan called for more research.

“It’s still early days,” he said. “We probably have more meta-analyses and systematic reviews of the field than we have primary research papers.

Dr. Cryan concluded his presentation on an optimistic note.

“Neurology is waking up ... to understand that the microbiome could be playing a key role in many, many other disorders. ... Overall, what we’re beginning to see is that our state of gut markedly affects our state of mind.”

Dr. Cryan disclosed relationships with Abbott Nutrition, Roche Pharma, Nutricia, and others.

A growing body of research links the gut with the brain and behavior, but compartmentalization within the medical community may be slowing investigation of the gut-brain axis, according to a leading expert.

Studies have shown that the microbiome may influence a diverse range of behavioral and neurological processes, from acute and chronic stress responses to development of Parkinson’s and Alzheimer’s disease, reported John F. Cryan, PhD, of University College Cork, Ireland.

Dr. Cryan began his presentation at the annual Gut Microbiota for Health World Summit by citing Hippocrates, who is thought to have stated that all diseases begin in the gut.

“That can be quite strange when I talk to my neurology or psychiatry colleagues,” Dr. Cryan said. “They sometimes look at me like I have two heads. Because in medicine we compartmentalize, and if you are studying neurology or psychiatry or [you are] in clinical practice, you are focusing on everything from the neck upwards.”

For more than a decade, Dr. Cryan and colleagues have been investigating the gut-brain axis, predominantly in mouse models, but also across animal species and in humans.

At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Cryan reviewed a variety of representative studies.

For instance, in both mice and humans, research has shown that C-section, which is associated with poorer microbiome diversity than vaginal delivery, has also been linked with social deficits and elevated stress responses. And in the case of mice, coprophagia, in which cesarean-delivered mice eat the feces of vaginally born mice, has been shown to ameliorate these psychiatric effects.

Dr. Cryan likened this process to an “artificial fecal transplant.”

“You know, co-housing and eating each other’s poo is not the translational approach that we were advocating by any means,” Dr. Cryan said. “But at least it tells us – in a proof-of-concept way – that if we change the microbiome, then we can reverse what’s going on.”

While the mechanisms behind the gut-brain axis remain incompletely understood, Dr. Cryan noted that the vagus nerve, which travels from the gut to the brain, plays a central role, and that transecting this nerve in mice stops the microbiome from affecting the brain.

“What happens in vagus doesn’t just stay in vagus, but will actually affect our emotions in different ways,” Dr. Cryan said.

He emphasized that communication travels both ways along the gut-brain axis, and went on to describe how this phenomenon has been demonstrated across a wide array of animals.

“From insects all the way through to primates, if you start to interfere with social behavior, you change the microbiome,” Dr. Cryan said. “But the opposite is also true; if you start to change the microbiome you can start to have widespread effects on social behavior.”

In humans, manipulating the microbiome could open up new psychiatric frontiers, Dr. Cryan said.

“[In the past 30 years], there really have been no real advances in how we manage mental health,” he said. “That’s very sobering when we are having such a mental health problem across all ages right now. And so perhaps it’s time for what we’ve coined the ‘psychobiotic revolution’ – time for a new way of thinking about mental health.”

According to Dr. Cryan, psychobiotics are interventions that target the microbiome for mental health purposes, including fermented foods, probiotics, prebiotics, synbiotics, parabiotics, and postbiotics.

Among these, probiotics have been a focal point of interventional research. Although results have been mixed, Dr. Cryan suggested that negative probiotic studies are more likely due to bacterial strain than a failure of the concept as a whole.

“Most strains of bacteria will do absolutely nothing,” Dr. Cryan said. “Strain is really important.”

In demonstration of this concept, he recounted a 2017 study conducted at University College Cork in which 22 healthy volunteers were given Bifidobacterium longum 1714, and then subjected to a social stress test. The results, published in Translational Psychiatry, showed that the probiotic, compared with placebo, was associated with attenuated stress responses, reduced daily stress, and enhanced visuospatial memory.

In contrast, a similar study by Dr. Cryan and colleagues, which tested Lactobacillus rhamnosus (JB-1), fell short.

“You [could not have gotten] more negative data into one paper if you tried,” Dr. Cryan said, referring to the study. “It did absolutely nothing.”

To find out which psychobiotics may have an impact, and how, Dr. Cryan called for more research.

“It’s still early days,” he said. “We probably have more meta-analyses and systematic reviews of the field than we have primary research papers.

Dr. Cryan concluded his presentation on an optimistic note.

“Neurology is waking up ... to understand that the microbiome could be playing a key role in many, many other disorders. ... Overall, what we’re beginning to see is that our state of gut markedly affects our state of mind.”

Dr. Cryan disclosed relationships with Abbott Nutrition, Roche Pharma, Nutricia, and others.

Higher out-of-pocket costs for prescription drugs are associated with poorer adherence across common neurologic conditions, a new study has found, suggesting that physicians should take patient costs into consideration when choosing which drugs to prescribe.

For their study, published online Feb. 19 in Neurology, Brian C. Callaghan, MD, of the University of Michigan, Ann Arbor, and colleagues looked at claims records from a large national private insurer to identify new cases of dementia, Parkinson’s disease, and neuropathy between 2001 and 2016, along with pharmacy records following diagnoses.

The researchers identified more than 52,000 patients with neuropathy on gabapentinoids and another 5,000 treated with serotonin-norepinephrine reuptake inhibitors for the same. They also identified some 20,000 patients with dementia taking cholinesterase inhibitors, and 3,000 with Parkinson’s disease taking dopamine agonists. Dr. Callaghan and colleagues compared patient adherence over 6 months for pairs of drugs in the same class with similar or equal efficacy, but with different costs to the patient.

Such cost differences can be stark: The researchers noted that the average 2016 out-of-pocket cost for 30 days of pregabalin, a drug used in the treatment of peripheral neuropathy, was $65.70, compared with $8.40 for gabapentin. With two common dementia drugs the difference was even more pronounced: $79.30 for rivastigmine compared with $3.10 for donepezil, both cholinesterase inhibitors with similar efficacy and tolerability.

Dr. Callaghan and colleagues found that such cost differences bore significantly on patient adherence. An increase of $50 in patient costs was seen decreasing adherence by 9% for neuropathy patients on gabapentinoids (adjusted incidence rate ratio [IRR] 0.91, 0.89-0.93) and by 12% for dementia patients on cholinesterase inhibitors (adjusted IRR 0.88, 0.86-0.91, P less than .05 for both). Similar price-linked decreases were seen for neuropathy patients on SNRIs and Parkinson’s patients on dopamine agonists, but the differences did not reach statistical significance.

Black, Asian, and Hispanic patients saw greater drops in adherence than did white patients associated with the same out-of-pocket cost differences, leading the researchers to note that special care should be taken in prescribing decisions for these populations.

“When choosing among medications with differential [out-of-pocket] costs, prescribing the medication with lower [out-of-pocket] expense will likely improve medication adherence while reducing overall costs,” Dr. Callaghan and colleagues wrote in their analysis. “For example, prescribing gabapentin or venlafaxine to patients with newly diagnosed neuropathy is likely to lead to higher adherence compared with pregabalin or duloxetine, and therefore, there is a higher likelihood of relief from neuropathic pain.” The researchers noted that while combination pills and extended-release formulations may be marketed as a way to increase adherence, the higher out-of-pocket costs of such medicines could offset any adherence benefit.

Dr. Callaghan and his colleagues described as strengths of their study its large sample and statistical approach that “allowed us to best estimate the causal relationship between [out-of-pocket] costs and medication adherence by limiting selection bias, residual confounding, and the confounding inherent to medication choice.” Nonadherence – patients who never filled a prescription after diagnosis – was not captured in the study.

The American Academy of Neurology funded the study. Two of its authors reported financial conflicts of interest in the form of compensation from pharmaceutical or device companies. Its lead author, Dr. Callaghan, reported funding for a device maker and performing medical legal consultations.

SOURCE: Reynolds EL et al. Neurology. 2020 Feb 19. doi/10.1212/WNL.0000000000009039.

Higher out-of-pocket costs for prescription drugs are associated with poorer adherence across common neurologic conditions, a new study has found, suggesting that physicians should take patient costs into consideration when choosing which drugs to prescribe.

For their study, published online Feb. 19 in Neurology, Brian C. Callaghan, MD, of the University of Michigan, Ann Arbor, and colleagues looked at claims records from a large national private insurer to identify new cases of dementia, Parkinson’s disease, and neuropathy between 2001 and 2016, along with pharmacy records following diagnoses.

The researchers identified more than 52,000 patients with neuropathy on gabapentinoids and another 5,000 treated with serotonin-norepinephrine reuptake inhibitors for the same. They also identified some 20,000 patients with dementia taking cholinesterase inhibitors, and 3,000 with Parkinson’s disease taking dopamine agonists. Dr. Callaghan and colleagues compared patient adherence over 6 months for pairs of drugs in the same class with similar or equal efficacy, but with different costs to the patient.

Such cost differences can be stark: The researchers noted that the average 2016 out-of-pocket cost for 30 days of pregabalin, a drug used in the treatment of peripheral neuropathy, was $65.70, compared with $8.40 for gabapentin. With two common dementia drugs the difference was even more pronounced: $79.30 for rivastigmine compared with $3.10 for donepezil, both cholinesterase inhibitors with similar efficacy and tolerability.

Dr. Callaghan and colleagues found that such cost differences bore significantly on patient adherence. An increase of $50 in patient costs was seen decreasing adherence by 9% for neuropathy patients on gabapentinoids (adjusted incidence rate ratio [IRR] 0.91, 0.89-0.93) and by 12% for dementia patients on cholinesterase inhibitors (adjusted IRR 0.88, 0.86-0.91, P less than .05 for both). Similar price-linked decreases were seen for neuropathy patients on SNRIs and Parkinson’s patients on dopamine agonists, but the differences did not reach statistical significance.

Black, Asian, and Hispanic patients saw greater drops in adherence than did white patients associated with the same out-of-pocket cost differences, leading the researchers to note that special care should be taken in prescribing decisions for these populations.

“When choosing among medications with differential [out-of-pocket] costs, prescribing the medication with lower [out-of-pocket] expense will likely improve medication adherence while reducing overall costs,” Dr. Callaghan and colleagues wrote in their analysis. “For example, prescribing gabapentin or venlafaxine to patients with newly diagnosed neuropathy is likely to lead to higher adherence compared with pregabalin or duloxetine, and therefore, there is a higher likelihood of relief from neuropathic pain.” The researchers noted that while combination pills and extended-release formulations may be marketed as a way to increase adherence, the higher out-of-pocket costs of such medicines could offset any adherence benefit.

Dr. Callaghan and his colleagues described as strengths of their study its large sample and statistical approach that “allowed us to best estimate the causal relationship between [out-of-pocket] costs and medication adherence by limiting selection bias, residual confounding, and the confounding inherent to medication choice.” Nonadherence – patients who never filled a prescription after diagnosis – was not captured in the study.

The American Academy of Neurology funded the study. Two of its authors reported financial conflicts of interest in the form of compensation from pharmaceutical or device companies. Its lead author, Dr. Callaghan, reported funding for a device maker and performing medical legal consultations.

SOURCE: Reynolds EL et al. Neurology. 2020 Feb 19. doi/10.1212/WNL.0000000000009039.

Higher out-of-pocket costs for prescription drugs are associated with poorer adherence across common neurologic conditions, a new study has found, suggesting that physicians should take patient costs into consideration when choosing which drugs to prescribe.

For their study, published online Feb. 19 in Neurology, Brian C. Callaghan, MD, of the University of Michigan, Ann Arbor, and colleagues looked at claims records from a large national private insurer to identify new cases of dementia, Parkinson’s disease, and neuropathy between 2001 and 2016, along with pharmacy records following diagnoses.

The researchers identified more than 52,000 patients with neuropathy on gabapentinoids and another 5,000 treated with serotonin-norepinephrine reuptake inhibitors for the same. They also identified some 20,000 patients with dementia taking cholinesterase inhibitors, and 3,000 with Parkinson’s disease taking dopamine agonists. Dr. Callaghan and colleagues compared patient adherence over 6 months for pairs of drugs in the same class with similar or equal efficacy, but with different costs to the patient.

Such cost differences can be stark: The researchers noted that the average 2016 out-of-pocket cost for 30 days of pregabalin, a drug used in the treatment of peripheral neuropathy, was $65.70, compared with $8.40 for gabapentin. With two common dementia drugs the difference was even more pronounced: $79.30 for rivastigmine compared with $3.10 for donepezil, both cholinesterase inhibitors with similar efficacy and tolerability.

Dr. Callaghan and colleagues found that such cost differences bore significantly on patient adherence. An increase of $50 in patient costs was seen decreasing adherence by 9% for neuropathy patients on gabapentinoids (adjusted incidence rate ratio [IRR] 0.91, 0.89-0.93) and by 12% for dementia patients on cholinesterase inhibitors (adjusted IRR 0.88, 0.86-0.91, P less than .05 for both). Similar price-linked decreases were seen for neuropathy patients on SNRIs and Parkinson’s patients on dopamine agonists, but the differences did not reach statistical significance.

Black, Asian, and Hispanic patients saw greater drops in adherence than did white patients associated with the same out-of-pocket cost differences, leading the researchers to note that special care should be taken in prescribing decisions for these populations.

“When choosing among medications with differential [out-of-pocket] costs, prescribing the medication with lower [out-of-pocket] expense will likely improve medication adherence while reducing overall costs,” Dr. Callaghan and colleagues wrote in their analysis. “For example, prescribing gabapentin or venlafaxine to patients with newly diagnosed neuropathy is likely to lead to higher adherence compared with pregabalin or duloxetine, and therefore, there is a higher likelihood of relief from neuropathic pain.” The researchers noted that while combination pills and extended-release formulations may be marketed as a way to increase adherence, the higher out-of-pocket costs of such medicines could offset any adherence benefit.

Dr. Callaghan and his colleagues described as strengths of their study its large sample and statistical approach that “allowed us to best estimate the causal relationship between [out-of-pocket] costs and medication adherence by limiting selection bias, residual confounding, and the confounding inherent to medication choice.” Nonadherence – patients who never filled a prescription after diagnosis – was not captured in the study.

The American Academy of Neurology funded the study. Two of its authors reported financial conflicts of interest in the form of compensation from pharmaceutical or device companies. Its lead author, Dr. Callaghan, reported funding for a device maker and performing medical legal consultations.

SOURCE: Reynolds EL et al. Neurology. 2020 Feb 19. doi/10.1212/WNL.0000000000009039.