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Robotic Pet Therapy in the Intensive Care Unit
Critical illness is commonly associated with interrelated conditions including pain, agitation, delirium, immobility, and sleep disruption (PADIS). Managing PADIS is often complex and includes pharmacologic and nonpharmacologic interventions.1 Incorporating multifaceted practices to enhance PADIS management has been shown to improve several intensive care unit (ICU)-related outcomes.2
Many pharmacologic PADIS treatments are ineffective or associated with adverse effects. For example, antipsychotics used for treating ICU-related delirium have not shown improved outcomes.3,4 Commonly used medications for agitation, such as benzodiazepines, increase delirium risk.5,6 Because of these limitations, several nonpharmacologic interventions for PADIS have been evaluated.
Pet therapy has been implemented in some ICU settings, but is not widely adopted.7 Also referred to as animal-assisted activities, animal-assisted therapy, or animal-assisted interventions, pet therapy typically involves interaction between a patient and a live animal (most commonly a dog) under the direction of an animal handler, with the intention of providing therapeutic benefit. Interactions frequently include meet and greet activities such as petting, but also could include walking or other activities. Pet therapy has been reported to reduce pain, agitation, and stress among ICU patients.8 Introducing a pet therapy program with live animals in the ICU could be challenging because of factors such as identifying trained, accredited animals and handlers, and managing infection control and other risks.9 As an alternative to live pets, robotic pet therapy has been shown to be beneficial—mostly outside the ICU—in settings such as long-term care.10,11 Although uncommon, robotic pets have been used in the ICU and hospital settings for therapeutic purposes.12 Robotic pets reduce many concerns associated with live animals while mimicking the behaviors of live animals and potentially offering many of the same benefits.
OBSERVATIONS
The North Florida/South Georgia Veterans Health System (NF/SGVHS) implemented a novel robotic pet therapy program for patients requiring ICU care to improve the treatment of PADIS. Funding was provided through a Veterans Health Administration Innovation Grant procured by a clinical pharmacy specialist as the program’s champion. Goals of the robotic pet therapy program include reductions in: distressing symptoms associated with PADIS, use of psychoactive drugs and physical restraints, and ICU length of stay. The ICU team developed standard operating procedures and an order menu, which were integrated into the ICU prescriber ordering menu. Patients were selected for pet therapy based on PADIS scores and potential for positive response to pet therapy as assessed by the ICU team.Patients in medical and surgical ICU settings were eligible for the program. The robotic pets used in the program were Joy for All Companion Pets (Ageless Innovation LLC). Robotic cats and dogs were available and pets were “adopted’ by each patient (Figure). As an infection control measure, pets were not reissued or shared amongpatients and pets could be cleaned with a disinfectant solution. Nurses were primarily responsible for monitoring and documenting responses to robotic pet therapy.
It was necessary to secure buy-in from several services to successfully implement the program. The critical care clinical pharmacy specialists were responsible for ordering, storing, and dispensing the robotic pets. The NF/SGVHS innovation specialist helped secure funding, procure the robotic pet, and promote the program. The standard operating procedures for the program were developed by a multidisciplinary team with input from critical care nurses, intensivists, pharmacists, patient safety, and infection control (Table 1). Success of the program also required buy-in from ICU team members.
Program Impact
A retrospective cohort study was conducted to assess for improvements in PADIS symptoms and medication use post-intervention. Patients were included if they received robotic pet therapy in the ICU from July 10, 2019, to February 1, 2021. Individuals aged < 18 years or > 89 years, were pregnant, or were not receiving ICU-level care were excluded. Outcomes assessed included improvement in pain scores, agitation scores, sleep quality, resolution of delirium, and use of pain or psychoactive medications during patients’ ICU stay.
Thirty patients were included in the study (Table 2). After receiving a robotic pet, 9 (30%) patients recorded decreased pain scores, 15 (50%) recorded decreased agitation scores, 8 (27%) had resolution of delirium, and 2 (7%) described improvement in sleep. Pain medication use decreased in 12 (40%) patients and psychoactive medication use was reduced in 7 (23%) patients.
Limitations
The robotic pet therapy program has shown promising results; however, some aspects merit discussion. Evaluation of this program is limited by factors such as the observational study design, single-center patient sample, and lack of comparator group. Although no known adverse effects of robotic pet therapy were seen, it is possible that some patients may not have a favorable response. Challenges of implementing a robotic pet therapy program include cost and additional operational activities (storage, ordering, dispensing) necessary to maintain the program. Additional research is needed to evaluate the impact of robotic pet therapy on other outcomes including cost, ICU length of stay, and patient satisfaction.
CONCLUSIONS
Robotic pet therapy can be successfully implemented in the ICU and appears to provide a simple, safe, beneficial, nonpharmacologic intervention for PADIS. This study showed that many patients had favorable response to robotic pet therapy, indicating that it may be a viable alternative to traditional pet therapy. Other health systems could benefit from implementing programs similar to the robotic pet therapy program at NF/SGVHS.
Acknowledgments
The author would like to acknowledge Simran Panesar, PharmD, and Theresa Faison, PharmD, for their contributions to this project.
1. Devlin JW, Skrobik Y, Gélinas C, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018;46:e825-e873. doi:10.1097/CCM.0000000000003299
2. Pun BT, Balas MC, Barnes-Daly MA, et al. Caring for critically ill patients with the ABCDEF bundle: results of the ICU Liberation Collaborative in over 15,000 adults. Crit Care Med. 2019;47:3-14. doi:10.1097/CCM.0000000000003482
3. Andersen-Ranberg NC, Poulsen LM, Perner A, et al; AID-ICU Trial Group. Haloperidol for the treatment of delirium in ICU patients. N Engl J Med. 2022;387:2425-2435. doi:10.1056/NEJMoa2211868
4. Girard TD, Exline MC, Carson SS, et al; MIND-USA Investigators. Haloperidol and ziprasidone for treatment of delirium in critical illness. N Engl J Med. 2018;379:2506-2516. doi:10.1056/NEJMoa1808217
5. Riker RR, Shehabi Y, Bokesch PM, et al; SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009;301:489-499. doi:10.1001/jama.2009.56
6. Pandharipande P, Shintani A, Peterson J, et al. Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology. 2006;104:21-26. doi:10.1097/00000542-200601000-00005
7. Society of Critical Care Medicine. ICU liberation bundle. Accessed February 27, 2024. https://www.sccm.org/ICULiberation/Home/ABCDEF-Bundles
8. Lovell T, Ranse K. Animal-assisted activities in the intensive care unit: a scoping review. Intensive Crit Care Nurs. 2022;73:103304. doi:10.1016/j.iccn.2022.103304
9. Hosey MM, Jaskulski J, Wegener ST, Chlan LL, Needham DM. Animal-assisted intervention in the ICU: a tool for humanization. Crit Care. 2018;22:22. doi:10.1186/s13054-018-1946-8
10. Jøranson N, Pedersen I, Rokstad AM, Ihlebæk C. Effects on symptoms of agitation and depression in persons with dementia participating in robot-assisted activity: a cluster-randomized controlled trial. J Am Med Dir Assoc. 2015;16:867-873. doi:10.1016/j.jamda.2015.05.002
11. Robinson H, Macdonald B, Kerse N, Broadbent E. The psychosocial effects of a companion robot: a randomized controlled trial. J Am Med Dir Assoc. 2013;14:661-667. doi:10.1016/j.jamda.2013.02.007
12. Schulman-Marcus J, Mookherjee S, Rice L, Lyubarova R. New approaches for the treatment of delirium: a case for robotic pets. Am J Med. 2019;132:781-782. doi:10.1016/j.amjmed.2018.12.039
Critical illness is commonly associated with interrelated conditions including pain, agitation, delirium, immobility, and sleep disruption (PADIS). Managing PADIS is often complex and includes pharmacologic and nonpharmacologic interventions.1 Incorporating multifaceted practices to enhance PADIS management has been shown to improve several intensive care unit (ICU)-related outcomes.2
Many pharmacologic PADIS treatments are ineffective or associated with adverse effects. For example, antipsychotics used for treating ICU-related delirium have not shown improved outcomes.3,4 Commonly used medications for agitation, such as benzodiazepines, increase delirium risk.5,6 Because of these limitations, several nonpharmacologic interventions for PADIS have been evaluated.
Pet therapy has been implemented in some ICU settings, but is not widely adopted.7 Also referred to as animal-assisted activities, animal-assisted therapy, or animal-assisted interventions, pet therapy typically involves interaction between a patient and a live animal (most commonly a dog) under the direction of an animal handler, with the intention of providing therapeutic benefit. Interactions frequently include meet and greet activities such as petting, but also could include walking or other activities. Pet therapy has been reported to reduce pain, agitation, and stress among ICU patients.8 Introducing a pet therapy program with live animals in the ICU could be challenging because of factors such as identifying trained, accredited animals and handlers, and managing infection control and other risks.9 As an alternative to live pets, robotic pet therapy has been shown to be beneficial—mostly outside the ICU—in settings such as long-term care.10,11 Although uncommon, robotic pets have been used in the ICU and hospital settings for therapeutic purposes.12 Robotic pets reduce many concerns associated with live animals while mimicking the behaviors of live animals and potentially offering many of the same benefits.
OBSERVATIONS
The North Florida/South Georgia Veterans Health System (NF/SGVHS) implemented a novel robotic pet therapy program for patients requiring ICU care to improve the treatment of PADIS. Funding was provided through a Veterans Health Administration Innovation Grant procured by a clinical pharmacy specialist as the program’s champion. Goals of the robotic pet therapy program include reductions in: distressing symptoms associated with PADIS, use of psychoactive drugs and physical restraints, and ICU length of stay. The ICU team developed standard operating procedures and an order menu, which were integrated into the ICU prescriber ordering menu. Patients were selected for pet therapy based on PADIS scores and potential for positive response to pet therapy as assessed by the ICU team.Patients in medical and surgical ICU settings were eligible for the program. The robotic pets used in the program were Joy for All Companion Pets (Ageless Innovation LLC). Robotic cats and dogs were available and pets were “adopted’ by each patient (Figure). As an infection control measure, pets were not reissued or shared amongpatients and pets could be cleaned with a disinfectant solution. Nurses were primarily responsible for monitoring and documenting responses to robotic pet therapy.
It was necessary to secure buy-in from several services to successfully implement the program. The critical care clinical pharmacy specialists were responsible for ordering, storing, and dispensing the robotic pets. The NF/SGVHS innovation specialist helped secure funding, procure the robotic pet, and promote the program. The standard operating procedures for the program were developed by a multidisciplinary team with input from critical care nurses, intensivists, pharmacists, patient safety, and infection control (Table 1). Success of the program also required buy-in from ICU team members.
Program Impact
A retrospective cohort study was conducted to assess for improvements in PADIS symptoms and medication use post-intervention. Patients were included if they received robotic pet therapy in the ICU from July 10, 2019, to February 1, 2021. Individuals aged < 18 years or > 89 years, were pregnant, or were not receiving ICU-level care were excluded. Outcomes assessed included improvement in pain scores, agitation scores, sleep quality, resolution of delirium, and use of pain or psychoactive medications during patients’ ICU stay.
Thirty patients were included in the study (Table 2). After receiving a robotic pet, 9 (30%) patients recorded decreased pain scores, 15 (50%) recorded decreased agitation scores, 8 (27%) had resolution of delirium, and 2 (7%) described improvement in sleep. Pain medication use decreased in 12 (40%) patients and psychoactive medication use was reduced in 7 (23%) patients.
Limitations
The robotic pet therapy program has shown promising results; however, some aspects merit discussion. Evaluation of this program is limited by factors such as the observational study design, single-center patient sample, and lack of comparator group. Although no known adverse effects of robotic pet therapy were seen, it is possible that some patients may not have a favorable response. Challenges of implementing a robotic pet therapy program include cost and additional operational activities (storage, ordering, dispensing) necessary to maintain the program. Additional research is needed to evaluate the impact of robotic pet therapy on other outcomes including cost, ICU length of stay, and patient satisfaction.
CONCLUSIONS
Robotic pet therapy can be successfully implemented in the ICU and appears to provide a simple, safe, beneficial, nonpharmacologic intervention for PADIS. This study showed that many patients had favorable response to robotic pet therapy, indicating that it may be a viable alternative to traditional pet therapy. Other health systems could benefit from implementing programs similar to the robotic pet therapy program at NF/SGVHS.
Acknowledgments
The author would like to acknowledge Simran Panesar, PharmD, and Theresa Faison, PharmD, for their contributions to this project.
Critical illness is commonly associated with interrelated conditions including pain, agitation, delirium, immobility, and sleep disruption (PADIS). Managing PADIS is often complex and includes pharmacologic and nonpharmacologic interventions.1 Incorporating multifaceted practices to enhance PADIS management has been shown to improve several intensive care unit (ICU)-related outcomes.2
Many pharmacologic PADIS treatments are ineffective or associated with adverse effects. For example, antipsychotics used for treating ICU-related delirium have not shown improved outcomes.3,4 Commonly used medications for agitation, such as benzodiazepines, increase delirium risk.5,6 Because of these limitations, several nonpharmacologic interventions for PADIS have been evaluated.
Pet therapy has been implemented in some ICU settings, but is not widely adopted.7 Also referred to as animal-assisted activities, animal-assisted therapy, or animal-assisted interventions, pet therapy typically involves interaction between a patient and a live animal (most commonly a dog) under the direction of an animal handler, with the intention of providing therapeutic benefit. Interactions frequently include meet and greet activities such as petting, but also could include walking or other activities. Pet therapy has been reported to reduce pain, agitation, and stress among ICU patients.8 Introducing a pet therapy program with live animals in the ICU could be challenging because of factors such as identifying trained, accredited animals and handlers, and managing infection control and other risks.9 As an alternative to live pets, robotic pet therapy has been shown to be beneficial—mostly outside the ICU—in settings such as long-term care.10,11 Although uncommon, robotic pets have been used in the ICU and hospital settings for therapeutic purposes.12 Robotic pets reduce many concerns associated with live animals while mimicking the behaviors of live animals and potentially offering many of the same benefits.
OBSERVATIONS
The North Florida/South Georgia Veterans Health System (NF/SGVHS) implemented a novel robotic pet therapy program for patients requiring ICU care to improve the treatment of PADIS. Funding was provided through a Veterans Health Administration Innovation Grant procured by a clinical pharmacy specialist as the program’s champion. Goals of the robotic pet therapy program include reductions in: distressing symptoms associated with PADIS, use of psychoactive drugs and physical restraints, and ICU length of stay. The ICU team developed standard operating procedures and an order menu, which were integrated into the ICU prescriber ordering menu. Patients were selected for pet therapy based on PADIS scores and potential for positive response to pet therapy as assessed by the ICU team.Patients in medical and surgical ICU settings were eligible for the program. The robotic pets used in the program were Joy for All Companion Pets (Ageless Innovation LLC). Robotic cats and dogs were available and pets were “adopted’ by each patient (Figure). As an infection control measure, pets were not reissued or shared amongpatients and pets could be cleaned with a disinfectant solution. Nurses were primarily responsible for monitoring and documenting responses to robotic pet therapy.
It was necessary to secure buy-in from several services to successfully implement the program. The critical care clinical pharmacy specialists were responsible for ordering, storing, and dispensing the robotic pets. The NF/SGVHS innovation specialist helped secure funding, procure the robotic pet, and promote the program. The standard operating procedures for the program were developed by a multidisciplinary team with input from critical care nurses, intensivists, pharmacists, patient safety, and infection control (Table 1). Success of the program also required buy-in from ICU team members.
Program Impact
A retrospective cohort study was conducted to assess for improvements in PADIS symptoms and medication use post-intervention. Patients were included if they received robotic pet therapy in the ICU from July 10, 2019, to February 1, 2021. Individuals aged < 18 years or > 89 years, were pregnant, or were not receiving ICU-level care were excluded. Outcomes assessed included improvement in pain scores, agitation scores, sleep quality, resolution of delirium, and use of pain or psychoactive medications during patients’ ICU stay.
Thirty patients were included in the study (Table 2). After receiving a robotic pet, 9 (30%) patients recorded decreased pain scores, 15 (50%) recorded decreased agitation scores, 8 (27%) had resolution of delirium, and 2 (7%) described improvement in sleep. Pain medication use decreased in 12 (40%) patients and psychoactive medication use was reduced in 7 (23%) patients.
Limitations
The robotic pet therapy program has shown promising results; however, some aspects merit discussion. Evaluation of this program is limited by factors such as the observational study design, single-center patient sample, and lack of comparator group. Although no known adverse effects of robotic pet therapy were seen, it is possible that some patients may not have a favorable response. Challenges of implementing a robotic pet therapy program include cost and additional operational activities (storage, ordering, dispensing) necessary to maintain the program. Additional research is needed to evaluate the impact of robotic pet therapy on other outcomes including cost, ICU length of stay, and patient satisfaction.
CONCLUSIONS
Robotic pet therapy can be successfully implemented in the ICU and appears to provide a simple, safe, beneficial, nonpharmacologic intervention for PADIS. This study showed that many patients had favorable response to robotic pet therapy, indicating that it may be a viable alternative to traditional pet therapy. Other health systems could benefit from implementing programs similar to the robotic pet therapy program at NF/SGVHS.
Acknowledgments
The author would like to acknowledge Simran Panesar, PharmD, and Theresa Faison, PharmD, for their contributions to this project.
1. Devlin JW, Skrobik Y, Gélinas C, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018;46:e825-e873. doi:10.1097/CCM.0000000000003299
2. Pun BT, Balas MC, Barnes-Daly MA, et al. Caring for critically ill patients with the ABCDEF bundle: results of the ICU Liberation Collaborative in over 15,000 adults. Crit Care Med. 2019;47:3-14. doi:10.1097/CCM.0000000000003482
3. Andersen-Ranberg NC, Poulsen LM, Perner A, et al; AID-ICU Trial Group. Haloperidol for the treatment of delirium in ICU patients. N Engl J Med. 2022;387:2425-2435. doi:10.1056/NEJMoa2211868
4. Girard TD, Exline MC, Carson SS, et al; MIND-USA Investigators. Haloperidol and ziprasidone for treatment of delirium in critical illness. N Engl J Med. 2018;379:2506-2516. doi:10.1056/NEJMoa1808217
5. Riker RR, Shehabi Y, Bokesch PM, et al; SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009;301:489-499. doi:10.1001/jama.2009.56
6. Pandharipande P, Shintani A, Peterson J, et al. Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology. 2006;104:21-26. doi:10.1097/00000542-200601000-00005
7. Society of Critical Care Medicine. ICU liberation bundle. Accessed February 27, 2024. https://www.sccm.org/ICULiberation/Home/ABCDEF-Bundles
8. Lovell T, Ranse K. Animal-assisted activities in the intensive care unit: a scoping review. Intensive Crit Care Nurs. 2022;73:103304. doi:10.1016/j.iccn.2022.103304
9. Hosey MM, Jaskulski J, Wegener ST, Chlan LL, Needham DM. Animal-assisted intervention in the ICU: a tool for humanization. Crit Care. 2018;22:22. doi:10.1186/s13054-018-1946-8
10. Jøranson N, Pedersen I, Rokstad AM, Ihlebæk C. Effects on symptoms of agitation and depression in persons with dementia participating in robot-assisted activity: a cluster-randomized controlled trial. J Am Med Dir Assoc. 2015;16:867-873. doi:10.1016/j.jamda.2015.05.002
11. Robinson H, Macdonald B, Kerse N, Broadbent E. The psychosocial effects of a companion robot: a randomized controlled trial. J Am Med Dir Assoc. 2013;14:661-667. doi:10.1016/j.jamda.2013.02.007
12. Schulman-Marcus J, Mookherjee S, Rice L, Lyubarova R. New approaches for the treatment of delirium: a case for robotic pets. Am J Med. 2019;132:781-782. doi:10.1016/j.amjmed.2018.12.039
1. Devlin JW, Skrobik Y, Gélinas C, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018;46:e825-e873. doi:10.1097/CCM.0000000000003299
2. Pun BT, Balas MC, Barnes-Daly MA, et al. Caring for critically ill patients with the ABCDEF bundle: results of the ICU Liberation Collaborative in over 15,000 adults. Crit Care Med. 2019;47:3-14. doi:10.1097/CCM.0000000000003482
3. Andersen-Ranberg NC, Poulsen LM, Perner A, et al; AID-ICU Trial Group. Haloperidol for the treatment of delirium in ICU patients. N Engl J Med. 2022;387:2425-2435. doi:10.1056/NEJMoa2211868
4. Girard TD, Exline MC, Carson SS, et al; MIND-USA Investigators. Haloperidol and ziprasidone for treatment of delirium in critical illness. N Engl J Med. 2018;379:2506-2516. doi:10.1056/NEJMoa1808217
5. Riker RR, Shehabi Y, Bokesch PM, et al; SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009;301:489-499. doi:10.1001/jama.2009.56
6. Pandharipande P, Shintani A, Peterson J, et al. Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology. 2006;104:21-26. doi:10.1097/00000542-200601000-00005
7. Society of Critical Care Medicine. ICU liberation bundle. Accessed February 27, 2024. https://www.sccm.org/ICULiberation/Home/ABCDEF-Bundles
8. Lovell T, Ranse K. Animal-assisted activities in the intensive care unit: a scoping review. Intensive Crit Care Nurs. 2022;73:103304. doi:10.1016/j.iccn.2022.103304
9. Hosey MM, Jaskulski J, Wegener ST, Chlan LL, Needham DM. Animal-assisted intervention in the ICU: a tool for humanization. Crit Care. 2018;22:22. doi:10.1186/s13054-018-1946-8
10. Jøranson N, Pedersen I, Rokstad AM, Ihlebæk C. Effects on symptoms of agitation and depression in persons with dementia participating in robot-assisted activity: a cluster-randomized controlled trial. J Am Med Dir Assoc. 2015;16:867-873. doi:10.1016/j.jamda.2015.05.002
11. Robinson H, Macdonald B, Kerse N, Broadbent E. The psychosocial effects of a companion robot: a randomized controlled trial. J Am Med Dir Assoc. 2013;14:661-667. doi:10.1016/j.jamda.2013.02.007
12. Schulman-Marcus J, Mookherjee S, Rice L, Lyubarova R. New approaches for the treatment of delirium: a case for robotic pets. Am J Med. 2019;132:781-782. doi:10.1016/j.amjmed.2018.12.039
Small Fiber Neuropathy in Veterans With Gulf War Illness
Following deployment to operations Desert Shield and Desert Storm (Gulf War) in 1990 and 1991, many Gulf War veterans (GWVs) developed chronic, complex symptoms, including pain, dyscognition, and fatigue, with gastrointestinal, skin, and respiratory manifestations. This Gulf War Illness (GWI) is reported to affect about 30% of those deployed. More than 30 years later, there is no consensus as to the etiology of GWI, although some deployment-related exposures have been implicated.1
Accepted research definitions for GWI include the Centers for Disease Control and Prevention and Kansas definitions.2 The US Department of Veterans Affairs (VA) uses the terminology chronic multisymptom illness (CMI), which is an overarching diagnosis under which GWI falls. Although there is no consensus case definition for CMI, there is overlap with conditions such as fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome, and irritable bowel syndrome; the VA considers these as qualifying clinical diagnoses.3 The pathophysiology of GWI is also unknown, though a frequently reported unifying feature is that of autonomic nervous system (ANS) dysfunction. Studies have demonstrated differences between veterans with GWI and those without GWI in both the reporting of symptoms attributable to ANS dysfunction and in physiologic evaluations of the ANS.4-10
Small fiber neuropathy (SFN), a condition with damage to the A-δ and C small nerve fibers, has been proposed as a potential mechanism for the pain and ANS dysfunction experienced in GWI.11-13 Symptoms of SFN are similar to those of GWI, with pain and ANS symptoms commonly reported.14,15 There are multiple diagnostic criteria for SFN, the most commonly used requiring the presence of appropriate symptoms in the absence of large fiber neuropathy and a skin biopsy demonstrating reduced intraepidermal nerve fiber density.16-19 Several conditions reportedly cause SFN, most notably diabetes/prediabetes. Autoimmune disease, vitamin B12 deficiency, monoclonal gammopathies, celiac disease, paraneoplastic syndromes, and sodium channel gene mutations may also contribute to SFN.20 Hyperlipidemia has been identified as a contributor, although it has been variably reported.21,22
Idiopathic neuropathies, SFN included, may be secondary to neurotoxicant exposures. Agents whose exposure or consumption have been associated with SFN include alcohol most prominently, but also the organic solvent n-hexane, heavy metals, and excess vitamin B6.20,23-25 Agents associated with large fiber neuropathy may also have relevance for SFN, as small fibers have been likened to the “canary in the coal mine” in that they may be more susceptible to neurotoxicants and are affected earlier in the disease process.26 In this way, SFN may be the harbinger of large fiber neuropathy in some cases. Of specific relevance for GWVs, organophosphates and carbamates are known to produce a delayed onset large fiber neuropathy.27-30 Exposure to petrochemical solvents has also been associated with large fiber neuropathies.31,32
The War Related Illness and Injury Study Center (WRIISC) is a clinical, research, and education center established by Congress in 2001. Its primary focus is on military exposures and postdeployment health of veterans. It is located at 3 sites: East Orange, New Jersey; Washington, DC; and Palo Alto, California. The New Jersey WRIISC began a program to evaluate GWVs with characteristic symptoms for possible SFN with use of a skin biopsy.
We hypothesize that SFN may underly much of GWI symptomatology and may not be accounted for by the putative etiologies detailed in review of the medical literature. This retrospective review of clinical evaluations for SFN in GWVs who sought care at the New Jersey WRIISC explored and addressed the following questions: (1) how common is biopsy-confirmed SFN in veterans with GWI; (2) do veterans with GWI and SFN report more symptoms attributable to ANS dysfunction when compared with veterans with GWI and no SFN; and (3) can SFN in veterans with GWI and SFN be explained by conditions and substances commonly associated with SFN? Institutional review board approval and waiver of consent was obtained from the Veterans Affairs New Jersey Health Care Center for the study.
Methods
A retrospective chart review was conducted on veterans evaluated at the WRIISC from March 1, 2015, to January 31, 2019. Inclusion criteria were: deployment to operations Desert Shield and Desert Storm between August 2, 1990, and February 28, 1991, and skin biopsy conducted at the WRIISC. Skin biopsies were obtained at the discretion of an examining clinician based on clinical indications, including neuropathic pain, ANS symptoms, and/or a fibromyalgia/chronic pain–type presentation.
Electronic health record review explicitly abstracted GWI status, results of the skin biopsy, and ANS symptom burden as determined by the Composite Autonomic Symptom Scale 31 (COMPASS 31) completed at the time of the WRIISC evaluation.
COMPASS 31 assesses symptoms across 6 domains (orthostatic, vasomotor, secretomotor, gastrointestinal, bladder, andpupillomotor). Patients are asked about symptom frequency (rarely to almost always), severity (mild to severe), and improvement (much worse to completely gone). Individual domain scores and a total weighted score (0-100) have demonstrated good validity, reliability, and consistency in SFN.33,34
In veterans with GWI and documented SFN, a health record review was performed to identify potential etiologies for SFN (Appendix).
Statistical Analysis
Microsoft Excel and IBM SPSS 12.0.1 for Windows were used for data collection and statistical analysis. Fisher exact test was used for comparing the prevalence of SFN in veterans with GWI vs without GWI. The independent samples t test was used for comparing COMPASS 31 scores for veterans with GWI by SFN status. α < .05 was used for determining statistical significance. For those GWVs documented with SFN and GWI, potential explanations were documented in total and by condition.
Results
From March 1, 2015, to January 31, 2019, 141 GWVs received a comprehensive in person clinical evaluation at the WRIISC and 51 veterans (36%) received a skin biopsy and were included in this retrospective observational study (Figure). The mean age was 48.6 years, and the majority were male and served in the US Army. Skin biopsies met clinical criteria for GWI for 42 (82%) and 24 of 42 (57%) were determined to have SFN. Four of 9 (44%) veterans without GWI had positive SFN biopsies, though this difference was not statistically significant (Table 1). Veterans with SFN but no GWI were not included in the further analysis.
Thirty-five veterans with GWI—18 with SFN and 17 without SFN—completed the COMPASS 31 (Table 2). COMPASS 31 data were not analyzed for veterans without GWI. Individual domain scores and the difference in COMPASS 31 scores for veterans with GWI and SFN vs GWI and no SFN (38.3 vs 37.8, respectively) were not statistically significant.
Sixteen of 24 veterans with GWI and SFN (67%) had ≥ 1 conditions that could potentially be responsible for SFN (Table 3), including 11 veterans (46%) with prediabetes/diabetes. Hyperlipidemia is only variably reported as a cause of SFN; when included, 19 of 24 (79%) SFN cases were accounted for. We could not identify a medical explanation for SFN in 5 of 24 veterans (21%) with GWI, which were deemed to be idiopathic.
Discussion
Biopsy-confirmed SFN was present in more than half of our sample of veterans with GWI, which is broadly consistent with what has been reported in the literature.13,35-38 In this clinical observation study, SFN was similarly prevalent in veterans with and without GWI; although it should be noted that biopsies only were obtained when there was a strong clinical suspicion for SFN. Almost half of patients with GWI did not have SFN, so our study does not support SFN as the underlying explanation for all GWI. Although our data cannot provide clinical guidance as to when skin biopsy may be indicated in GWI, work done in fibromyalgia found symptoms of dysautonomia and paresthesias are more specific for SFN and may be useful to help guide medical decision making.39
Veterans with GWI in our clinical sample reported a high burden of clinical symptoms conceivably attributable to ANS dysfunction. This symptom reporting is consistent with that seen in other GWI studies, as well as in other studies of SFN.4,5,7-9,14,15,34,38,40 Our clinical sample of veterans with GWI found no differences in the ANS symptom reporting between those with and without SFN. Therefore, our study cannot support SFN alone as accounting for ANS symptom burden in patients with GWI.
Two-thirds of biopsy-confirmed SFN in our clinical sample of veterans with GWI could potentially be explained by established medical conditions. As in other studies of SFN, prediabetes and diabetes represented a plurality (46%). Even after considering hyperlipidemia as a potential explanation, about 21% of SFN cases in veterans with GWI still were deemed idiopathic.
Evidence supports certain environmental agents as causal factors for GWI. Neurotoxicants reportedly related to GWI include pesticides (particularly organophosphates and carbamates), pyridostigmine bromide (used during the Gulf War as a prophylactic agent against the use of chemical weapons), and low levels of the nerve agent sarin from environmental contamination due to chemical weapons detonations.1 Some of these agents have been implicated in neuropathy as well.1,28-30 It is biologically plausible that deployment-related exposures could trigger SFN, though the traditional consensus has been that remote exposure to neurotoxic substances is unlikely to produce neuropathy that presents many years after the exposure.41 In the WRIISC clinical experience, however, veterans often report that their neuropathic symptoms predate the diagnosis of the associated medical conditions, sometimes by decades. It is conceivable that remote exposures may trigger the condition that is then potentiated by ongoing exposures, metabolic factors, and/or other medical conditions. These may perpetuate neuropathic symptoms and the illness experience of affected veterans. Our clinical observation study cannot clarify the extent to which this may be the case. Despite these findings and arguments, an environmental contribution to SFN cannot be discounted, and further research is needed to explore a potential relationship.
Limitations
This study’s conclusions are limited by its observational/retrospective design in a relatively small clinical sample of veterans evaluated at a tertiary referral center for postdeployment exposure-related health concerns. The WRIISC clinical sample is not representative of all GWVs or even of all veterans with GWI, as there is inherent selection bias as to who gets referred to and evaluated at the WRIISC. As with studies based on retrospective chart review, data are reliant on clinical documentation andaccuracy/consistency of the reviewer. Evaluation for SFN with skin biopsy is an invasive procedure and was performed when a high index of clinical suspicion for this condition existed, possibly representing confirmation bias. Therefore, the relatively high prevalence ofbiopsy-confirmed SFN seen in our clinical sample cannot be generalized to GWVs as a whole or even to veterans with GWI.
Assessment of autonomic dysfunction was based on COMPASS 31 symptom reporting by an small subset of the clinical cohort. Symptom reporting may not be reflective of true abnormality in ANS function. Physiologic tests of the ANS were not performed; such studies could more objectively establish whether ANS dysfunction is more prevalent in GWI veterans with SFN.
Evaluation for all potential etiologic/contributory conditions to SFN was not exhaustive. For example, sodium channel gene mutations have been documented to account for up to one-third of all cases of idiopathic SFN.42 For those cases in which no compelling etiology was identified, it is plausible that medical explanations for SFN may be found on further investigation.
Clinical assessments at the WRIISC were performed on GWVs ≥ 26 years after their deployment-related exposures. Other conditions/exposures may have occurred in the interim. What is not clear is whether the SFN predated the onset of any of these medical conditions or other putative contributors. This observational study is not able to tease out a temporal association to make a cause-and-effect assessment.
Conclusions
Retrospective analysis of clinical data of veterans evaluated at a specialized center for postdeployment health demonstrated that skin biopsy–confirmed SFN was prevalent, but not ubiquitous, in veterans with GWI. Symptom that may be attributed to ANS dysfunction in this clinical sample was consistent with literature on SFN and with GWI, but we could not definitively attribute ANS symptoms to SFN. Our study does not support the hypothesis that GWI symptoms are solely due to SFN, though it may still be relevant in a subset of veterans with GWI with strongly suggestive clinical features. We were able to identify a potential etiology for SFN in most veterans with GWI. Further investigations are recommended to explore any potential relationship between Gulf War exposures and SFN.
1. White RF, Steele L, O’Callaghan JP, et al. Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: effects of toxicant exposures during deployment. Cortex. 2016;74:449-475. doi:10.1016/j.cortex.2015.08.022
2. Committee on the Development of a Consensus Case Definition for Chronic Multisymptom Illness in 1990-1991 Gulf War Veterans, Board on the Health of Select Populations, Institute of Medicine. Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined. National Academies Press; 2014.
3. Robbins R, Helmer D, Monahan P, et al. Management of chronic multisymptom illness: synopsis of the 2021 US Department of Veterans Affairs and US Department of Defense Clinical Practice Guideline. Mayo Clin Proc. 2022;97(5):991-1002. doi:10.1016/j.mayocp.2022.01.031
4. Fox A, Helmer D, Tseng CL, Patrick-DeLuca L, Osinubi O. Report of autonomic symptoms in a clinical sample of veterans with Gulf War Illness. Mil Med. 2018;183(3-4):e179-e185. doi:10.1093/milmed/usx052
5. Fox A, Helmer D, Tseng CL, McCarron K, Satcher S, Osinubi O. Autonomic symptoms in Gulf War veterans evaluated at the War Related Illness and Injury Study Center. Mil Med. 2019;184(3-4):e191-e196. doi:10.1093/milmed/usy227
6. Reyes L, Falvo M, Blatt M, Ghobreal B, Acosta A, Serrador J. Autonomic dysfunction in veterans with Gulf War illness [abstract]. FASEB J. 2014;28(S1):1068.19. doi:10.1096/fasebj.28.1_supplement.1068.19
7. Haley RW, Charuvastra E, Shell WE, et al. Cholinergic autonomic dysfunction in veterans with Gulf War illness: confirmation in a population-based sample. JAMA Neurol. 2013;70(2):191-200. doi:10.1001/jamaneurol.2013.596
8. Haley RW, Vongpatanasin W, Wolfe GI, et al. Blunted circadian variation in autonomic regulation of sinus node function in veterans with Gulf War syndrome. Am J Med. 2004;117(7):469-478. doi:10.1016/j.amjmed.2004.03.041
9. Avery TJ, Mathersul DC, Schulz-Heik RJ, Mahoney L, Bayley PJ. Self-reported autonomic dysregulation in Gulf War Illness. Mil Med. Published online December 30, 2021. doi:10.1093/milmed/usab546
10. Verne ZT, Fields JZ, Zhang BB, Zhou Q. Autonomic dysfunction and gastroparesis in Gulf War veterans. J Investig Med. 2023;71(1):7-10. doi:10.1136/jim-2021-002291
11. Levine TD. Small fiber neuropathy: disease classification beyond pain and burning. J Cent Nerv Syst Dis. 2018;10:1179573518771703. doi:10.1177/1179573518771703
12. Novak P. Autonomic disorders. Am J Med. 2019;132(4):420-436. doi:10.1016/j.amjmed.2018.09.027
13. Oaklander AL, Klein MM. Undiagnosed small-fiber polyneuropathy: is it a component of Gulf War Illness? Defense Technical Information Center. Accessed February 21, 2024. https://apps.dtic.mil/sti/citations/ADA613891
14. Sène D. Small fiber neuropathy: diagnosis, causes, and treatment. Joint Bone Spine. 2018;85(5):553-559. doi:10.1016/j.jbspin.2017.11.002
15. Novak V, Freimer ML, Kissel JT, et al. Autonomic impairment in painful neuropathy. Neurology. 2001;56(7):861-868. doi:10.1212/wnl.56.7.861
16. Myers MI, Peltier AC. Uses of skin biopsy for sensory and autonomic nerve assessment. Curr Neurol Neurosci Rep. 2013;13(1):323. doi:10.1007/s11910-012-0323-2
17. Haroutounian S, Todorovic MS, Leinders M, et al. Diagnostic criteria for idiopathic small fiber neuropathy: a systematic review. Muscle Nerve. 2021;63(2):170-177. doi:10.1002/mus.27070
18. Levine TD, Saperstein DS. Routine use of punch biopsy to diagnose small fiber neuropathy in fibromyalgia patients. Clin Rheumatol. 2015;34(3):413-417. doi:10.1007/s10067-014-2850-5
19. England JD, Gronseth G S, Franklin G, et al. Practice parameter: the evaluation of distal symmetric polyneuropathy: the role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. PM R. 2009;1(1):14-22. doi:10.1016/j.pmrj.2008.11.011
20. de Greef BTA, Hoeijmakers JGJ, Gorissen-Brouwers CML, Geerts M, Faber CG, Merkies ISJ. Associated conditions in small fiber neuropathy - a large cohort study and review of the literature. Eur J Neurol. 2018;25(2):348-355. doi:10.1111/ene.13508
21. Morkavuk G, Leventoglu A. Small fiber neuropathy associated with hyperlipidemia: utility of cutaneous silent periods and autonomic tests. ISRN Neurol. 2014;2014:579242. doi:10.1155/2014/579242
22. Bednarik J, Vlckova-Moravcova E, Bursova S, Belobradkova J, Dusek L, Sommer C. Etiology of small-fiber neuropathy. J Peripher Nerv Syst. 2009;14(3):177-183. doi:10.1111/j.1529-8027.2009.00229.x
23. Kokotis P, Papantoniou M, Schmelz M, Buntziouka C, Tzavellas E, Paparrigopoulos T. Pure small fiber neuropathy in alcohol dependency detected by skin biopsy. Alcohol Fayettev N. 2023;111:67-73. doi:10.1016/j.alcohol.2023.05.006
24. Guimarães-Costa R, Schoindre Y, Metlaine A, et al. N-hexane exposure: a cause of small fiber neuropathy. J Peripher Nerv Syst. 2018;23(2):143-146. doi:10.1111/jns.12261
25. Koszewicz M, Markowska K, Waliszewska-Prosol M, et al. The impact of chronic co-exposure to different heavy metals on small fibers of peripheral nerves. A study of metal industry workers. J Occup Med Toxicol. 2021;16(1):12. doi:10.1186/s12995-021-00302-6
26. Johns Hopkins Medicine. Small nerve fibers defy neuropathy conventions. April 11, 2016. Accessed February 21, 2024. https://www.hopkinsmedicine.org/news/media/releases/small_nerve_fibers_defy_neuropathy_conventions
27. Jett DA. Neurotoxic pesticides and neurologic effects. Neurol Clin. 2011;29(3):667-677. doi:10.1016/j.ncl.2011.06.002
28. Berger AR, Schaumburg HH. Human toxic neuropathy caused by industrial agents. In: Dyck PJ, Thomas PK, eds. Peripheral Neuropathy. 4th ed. Saunders; 2005:2505-2525. doi:10.1016/B978-0-7216-9491-7.50115-0
29. Herskovitz S, Schaumburg HH. Neuropathy caused by drugs. In: Dyck PJ, Thomas PK, eds. Peripheral Neuropathy. 4th ed. Saunders; 2005:2553-2583.
30. Katona I, Weis J. Chapter 31 - Diseases of the peripheral nerves. Handb Clin Neurol. 2017;145:453-474. doi:10.1016/B978-0-12-802395-2.00031-6
31. Matikainen E, Juntunen J. Autonomic nervous system dysfunction in workers exposed to organic solvents. J Neurol Neurosurg Psychiatry. 1985;48(10):1021-1024. doi:10.1136/jnnp.48.10.1021
32. Murata K, Araki S, Yokoyama K, Maeda K. Autonomic and peripheral nervous system dysfunction in workers exposed to mixed organic solvents. Int Arch Occup Environ Health. 1991;63(5):335-340. doi:10.1007/BF00381584
33. Sletten DM, Suarez GA, Low PA, Mandrekar J, Singer W. COMPASS 31: a refined and abbreviated Composite Autonomic Symptom Score. Mayo Clin Proc. 2012;87(12):1196-1201. doi:10.1016/j.mayocp.2012.10.013
34. Treister R, O’Neil K, Downs HM, Oaklander AL. Validation of the Composite Autonomic Symptom Scale-31 (COMPASS-31) in patients with and without small-fiber polyneuropathy. Eur J Neurol. 2015;22(7):1124-1130. doi:10.1111/ene.12717
35. Joseph P, Arevalo C, Oliveira RKF, et al. Insights from invasive cardiopulmonary exercise testing of patients with myalgic encephalomyelitis/chronic fatigue syndrome. Chest. 2021;160(2):642-651. doi:10.1016/j.chest.2021.01.082
36. Giannoccaro MP, Donadio V, Incensi A, Avoni P, Liguori R. Small nerve fiber involvement in patients referred for fibromyalgia. Muscle Nerve. 2014;49(5):757-759. doi:10.1002/mus.24156
37. Oaklander AL, Herzog ZD, Downs HM, Klein MM. Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain. 2013;154(11):2310-2316. doi:10.1016/j.pain.2013.06.001
38. Serrador JM. Diagnosis of late-stage, early-onset, small-fiber polyneuropathy. Defense Technical Information Center. December 1, 2019. Accessed February 21, 2024. https://apps.dtic.mil/sti/citations/AD1094831
39. Lodahl M, Treister R, Oaklander AL. Specific symptoms may discriminate between fibromyalgia patients with vs without objective test evidence of small-fiber polyneuropathy. Pain Rep. 2018;3(1):e633. doi:10.1097/PR9.0000000000000633
40. Sastre A, Cook MR. Autonomic dysfunction in Gulf War veterans. Defense Technical Information Center. April 1, 2004. Accessed February 21, 2024. https://apps.dtic.mil/sti/citations/ADA429525
41. Little AA, Albers JW. Clinical description of toxic neuropathies. Handb Clin Neurol. 2015;131:253-296. doi:10.1016/B978-0-444-62627-1.00015-9
42. Faber CG, Hoeijmakers JGJ, Ahn HS, et al. Gain of function NaV1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol. 2012;71(1):26-39.
Following deployment to operations Desert Shield and Desert Storm (Gulf War) in 1990 and 1991, many Gulf War veterans (GWVs) developed chronic, complex symptoms, including pain, dyscognition, and fatigue, with gastrointestinal, skin, and respiratory manifestations. This Gulf War Illness (GWI) is reported to affect about 30% of those deployed. More than 30 years later, there is no consensus as to the etiology of GWI, although some deployment-related exposures have been implicated.1
Accepted research definitions for GWI include the Centers for Disease Control and Prevention and Kansas definitions.2 The US Department of Veterans Affairs (VA) uses the terminology chronic multisymptom illness (CMI), which is an overarching diagnosis under which GWI falls. Although there is no consensus case definition for CMI, there is overlap with conditions such as fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome, and irritable bowel syndrome; the VA considers these as qualifying clinical diagnoses.3 The pathophysiology of GWI is also unknown, though a frequently reported unifying feature is that of autonomic nervous system (ANS) dysfunction. Studies have demonstrated differences between veterans with GWI and those without GWI in both the reporting of symptoms attributable to ANS dysfunction and in physiologic evaluations of the ANS.4-10
Small fiber neuropathy (SFN), a condition with damage to the A-δ and C small nerve fibers, has been proposed as a potential mechanism for the pain and ANS dysfunction experienced in GWI.11-13 Symptoms of SFN are similar to those of GWI, with pain and ANS symptoms commonly reported.14,15 There are multiple diagnostic criteria for SFN, the most commonly used requiring the presence of appropriate symptoms in the absence of large fiber neuropathy and a skin biopsy demonstrating reduced intraepidermal nerve fiber density.16-19 Several conditions reportedly cause SFN, most notably diabetes/prediabetes. Autoimmune disease, vitamin B12 deficiency, monoclonal gammopathies, celiac disease, paraneoplastic syndromes, and sodium channel gene mutations may also contribute to SFN.20 Hyperlipidemia has been identified as a contributor, although it has been variably reported.21,22
Idiopathic neuropathies, SFN included, may be secondary to neurotoxicant exposures. Agents whose exposure or consumption have been associated with SFN include alcohol most prominently, but also the organic solvent n-hexane, heavy metals, and excess vitamin B6.20,23-25 Agents associated with large fiber neuropathy may also have relevance for SFN, as small fibers have been likened to the “canary in the coal mine” in that they may be more susceptible to neurotoxicants and are affected earlier in the disease process.26 In this way, SFN may be the harbinger of large fiber neuropathy in some cases. Of specific relevance for GWVs, organophosphates and carbamates are known to produce a delayed onset large fiber neuropathy.27-30 Exposure to petrochemical solvents has also been associated with large fiber neuropathies.31,32
The War Related Illness and Injury Study Center (WRIISC) is a clinical, research, and education center established by Congress in 2001. Its primary focus is on military exposures and postdeployment health of veterans. It is located at 3 sites: East Orange, New Jersey; Washington, DC; and Palo Alto, California. The New Jersey WRIISC began a program to evaluate GWVs with characteristic symptoms for possible SFN with use of a skin biopsy.
We hypothesize that SFN may underly much of GWI symptomatology and may not be accounted for by the putative etiologies detailed in review of the medical literature. This retrospective review of clinical evaluations for SFN in GWVs who sought care at the New Jersey WRIISC explored and addressed the following questions: (1) how common is biopsy-confirmed SFN in veterans with GWI; (2) do veterans with GWI and SFN report more symptoms attributable to ANS dysfunction when compared with veterans with GWI and no SFN; and (3) can SFN in veterans with GWI and SFN be explained by conditions and substances commonly associated with SFN? Institutional review board approval and waiver of consent was obtained from the Veterans Affairs New Jersey Health Care Center for the study.
Methods
A retrospective chart review was conducted on veterans evaluated at the WRIISC from March 1, 2015, to January 31, 2019. Inclusion criteria were: deployment to operations Desert Shield and Desert Storm between August 2, 1990, and February 28, 1991, and skin biopsy conducted at the WRIISC. Skin biopsies were obtained at the discretion of an examining clinician based on clinical indications, including neuropathic pain, ANS symptoms, and/or a fibromyalgia/chronic pain–type presentation.
Electronic health record review explicitly abstracted GWI status, results of the skin biopsy, and ANS symptom burden as determined by the Composite Autonomic Symptom Scale 31 (COMPASS 31) completed at the time of the WRIISC evaluation.
COMPASS 31 assesses symptoms across 6 domains (orthostatic, vasomotor, secretomotor, gastrointestinal, bladder, andpupillomotor). Patients are asked about symptom frequency (rarely to almost always), severity (mild to severe), and improvement (much worse to completely gone). Individual domain scores and a total weighted score (0-100) have demonstrated good validity, reliability, and consistency in SFN.33,34
In veterans with GWI and documented SFN, a health record review was performed to identify potential etiologies for SFN (Appendix).
Statistical Analysis
Microsoft Excel and IBM SPSS 12.0.1 for Windows were used for data collection and statistical analysis. Fisher exact test was used for comparing the prevalence of SFN in veterans with GWI vs without GWI. The independent samples t test was used for comparing COMPASS 31 scores for veterans with GWI by SFN status. α < .05 was used for determining statistical significance. For those GWVs documented with SFN and GWI, potential explanations were documented in total and by condition.
Results
From March 1, 2015, to January 31, 2019, 141 GWVs received a comprehensive in person clinical evaluation at the WRIISC and 51 veterans (36%) received a skin biopsy and were included in this retrospective observational study (Figure). The mean age was 48.6 years, and the majority were male and served in the US Army. Skin biopsies met clinical criteria for GWI for 42 (82%) and 24 of 42 (57%) were determined to have SFN. Four of 9 (44%) veterans without GWI had positive SFN biopsies, though this difference was not statistically significant (Table 1). Veterans with SFN but no GWI were not included in the further analysis.
Thirty-five veterans with GWI—18 with SFN and 17 without SFN—completed the COMPASS 31 (Table 2). COMPASS 31 data were not analyzed for veterans without GWI. Individual domain scores and the difference in COMPASS 31 scores for veterans with GWI and SFN vs GWI and no SFN (38.3 vs 37.8, respectively) were not statistically significant.
Sixteen of 24 veterans with GWI and SFN (67%) had ≥ 1 conditions that could potentially be responsible for SFN (Table 3), including 11 veterans (46%) with prediabetes/diabetes. Hyperlipidemia is only variably reported as a cause of SFN; when included, 19 of 24 (79%) SFN cases were accounted for. We could not identify a medical explanation for SFN in 5 of 24 veterans (21%) with GWI, which were deemed to be idiopathic.
Discussion
Biopsy-confirmed SFN was present in more than half of our sample of veterans with GWI, which is broadly consistent with what has been reported in the literature.13,35-38 In this clinical observation study, SFN was similarly prevalent in veterans with and without GWI; although it should be noted that biopsies only were obtained when there was a strong clinical suspicion for SFN. Almost half of patients with GWI did not have SFN, so our study does not support SFN as the underlying explanation for all GWI. Although our data cannot provide clinical guidance as to when skin biopsy may be indicated in GWI, work done in fibromyalgia found symptoms of dysautonomia and paresthesias are more specific for SFN and may be useful to help guide medical decision making.39
Veterans with GWI in our clinical sample reported a high burden of clinical symptoms conceivably attributable to ANS dysfunction. This symptom reporting is consistent with that seen in other GWI studies, as well as in other studies of SFN.4,5,7-9,14,15,34,38,40 Our clinical sample of veterans with GWI found no differences in the ANS symptom reporting between those with and without SFN. Therefore, our study cannot support SFN alone as accounting for ANS symptom burden in patients with GWI.
Two-thirds of biopsy-confirmed SFN in our clinical sample of veterans with GWI could potentially be explained by established medical conditions. As in other studies of SFN, prediabetes and diabetes represented a plurality (46%). Even after considering hyperlipidemia as a potential explanation, about 21% of SFN cases in veterans with GWI still were deemed idiopathic.
Evidence supports certain environmental agents as causal factors for GWI. Neurotoxicants reportedly related to GWI include pesticides (particularly organophosphates and carbamates), pyridostigmine bromide (used during the Gulf War as a prophylactic agent against the use of chemical weapons), and low levels of the nerve agent sarin from environmental contamination due to chemical weapons detonations.1 Some of these agents have been implicated in neuropathy as well.1,28-30 It is biologically plausible that deployment-related exposures could trigger SFN, though the traditional consensus has been that remote exposure to neurotoxic substances is unlikely to produce neuropathy that presents many years after the exposure.41 In the WRIISC clinical experience, however, veterans often report that their neuropathic symptoms predate the diagnosis of the associated medical conditions, sometimes by decades. It is conceivable that remote exposures may trigger the condition that is then potentiated by ongoing exposures, metabolic factors, and/or other medical conditions. These may perpetuate neuropathic symptoms and the illness experience of affected veterans. Our clinical observation study cannot clarify the extent to which this may be the case. Despite these findings and arguments, an environmental contribution to SFN cannot be discounted, and further research is needed to explore a potential relationship.
Limitations
This study’s conclusions are limited by its observational/retrospective design in a relatively small clinical sample of veterans evaluated at a tertiary referral center for postdeployment exposure-related health concerns. The WRIISC clinical sample is not representative of all GWVs or even of all veterans with GWI, as there is inherent selection bias as to who gets referred to and evaluated at the WRIISC. As with studies based on retrospective chart review, data are reliant on clinical documentation andaccuracy/consistency of the reviewer. Evaluation for SFN with skin biopsy is an invasive procedure and was performed when a high index of clinical suspicion for this condition existed, possibly representing confirmation bias. Therefore, the relatively high prevalence ofbiopsy-confirmed SFN seen in our clinical sample cannot be generalized to GWVs as a whole or even to veterans with GWI.
Assessment of autonomic dysfunction was based on COMPASS 31 symptom reporting by an small subset of the clinical cohort. Symptom reporting may not be reflective of true abnormality in ANS function. Physiologic tests of the ANS were not performed; such studies could more objectively establish whether ANS dysfunction is more prevalent in GWI veterans with SFN.
Evaluation for all potential etiologic/contributory conditions to SFN was not exhaustive. For example, sodium channel gene mutations have been documented to account for up to one-third of all cases of idiopathic SFN.42 For those cases in which no compelling etiology was identified, it is plausible that medical explanations for SFN may be found on further investigation.
Clinical assessments at the WRIISC were performed on GWVs ≥ 26 years after their deployment-related exposures. Other conditions/exposures may have occurred in the interim. What is not clear is whether the SFN predated the onset of any of these medical conditions or other putative contributors. This observational study is not able to tease out a temporal association to make a cause-and-effect assessment.
Conclusions
Retrospective analysis of clinical data of veterans evaluated at a specialized center for postdeployment health demonstrated that skin biopsy–confirmed SFN was prevalent, but not ubiquitous, in veterans with GWI. Symptom that may be attributed to ANS dysfunction in this clinical sample was consistent with literature on SFN and with GWI, but we could not definitively attribute ANS symptoms to SFN. Our study does not support the hypothesis that GWI symptoms are solely due to SFN, though it may still be relevant in a subset of veterans with GWI with strongly suggestive clinical features. We were able to identify a potential etiology for SFN in most veterans with GWI. Further investigations are recommended to explore any potential relationship between Gulf War exposures and SFN.
Following deployment to operations Desert Shield and Desert Storm (Gulf War) in 1990 and 1991, many Gulf War veterans (GWVs) developed chronic, complex symptoms, including pain, dyscognition, and fatigue, with gastrointestinal, skin, and respiratory manifestations. This Gulf War Illness (GWI) is reported to affect about 30% of those deployed. More than 30 years later, there is no consensus as to the etiology of GWI, although some deployment-related exposures have been implicated.1
Accepted research definitions for GWI include the Centers for Disease Control and Prevention and Kansas definitions.2 The US Department of Veterans Affairs (VA) uses the terminology chronic multisymptom illness (CMI), which is an overarching diagnosis under which GWI falls. Although there is no consensus case definition for CMI, there is overlap with conditions such as fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome, and irritable bowel syndrome; the VA considers these as qualifying clinical diagnoses.3 The pathophysiology of GWI is also unknown, though a frequently reported unifying feature is that of autonomic nervous system (ANS) dysfunction. Studies have demonstrated differences between veterans with GWI and those without GWI in both the reporting of symptoms attributable to ANS dysfunction and in physiologic evaluations of the ANS.4-10
Small fiber neuropathy (SFN), a condition with damage to the A-δ and C small nerve fibers, has been proposed as a potential mechanism for the pain and ANS dysfunction experienced in GWI.11-13 Symptoms of SFN are similar to those of GWI, with pain and ANS symptoms commonly reported.14,15 There are multiple diagnostic criteria for SFN, the most commonly used requiring the presence of appropriate symptoms in the absence of large fiber neuropathy and a skin biopsy demonstrating reduced intraepidermal nerve fiber density.16-19 Several conditions reportedly cause SFN, most notably diabetes/prediabetes. Autoimmune disease, vitamin B12 deficiency, monoclonal gammopathies, celiac disease, paraneoplastic syndromes, and sodium channel gene mutations may also contribute to SFN.20 Hyperlipidemia has been identified as a contributor, although it has been variably reported.21,22
Idiopathic neuropathies, SFN included, may be secondary to neurotoxicant exposures. Agents whose exposure or consumption have been associated with SFN include alcohol most prominently, but also the organic solvent n-hexane, heavy metals, and excess vitamin B6.20,23-25 Agents associated with large fiber neuropathy may also have relevance for SFN, as small fibers have been likened to the “canary in the coal mine” in that they may be more susceptible to neurotoxicants and are affected earlier in the disease process.26 In this way, SFN may be the harbinger of large fiber neuropathy in some cases. Of specific relevance for GWVs, organophosphates and carbamates are known to produce a delayed onset large fiber neuropathy.27-30 Exposure to petrochemical solvents has also been associated with large fiber neuropathies.31,32
The War Related Illness and Injury Study Center (WRIISC) is a clinical, research, and education center established by Congress in 2001. Its primary focus is on military exposures and postdeployment health of veterans. It is located at 3 sites: East Orange, New Jersey; Washington, DC; and Palo Alto, California. The New Jersey WRIISC began a program to evaluate GWVs with characteristic symptoms for possible SFN with use of a skin biopsy.
We hypothesize that SFN may underly much of GWI symptomatology and may not be accounted for by the putative etiologies detailed in review of the medical literature. This retrospective review of clinical evaluations for SFN in GWVs who sought care at the New Jersey WRIISC explored and addressed the following questions: (1) how common is biopsy-confirmed SFN in veterans with GWI; (2) do veterans with GWI and SFN report more symptoms attributable to ANS dysfunction when compared with veterans with GWI and no SFN; and (3) can SFN in veterans with GWI and SFN be explained by conditions and substances commonly associated with SFN? Institutional review board approval and waiver of consent was obtained from the Veterans Affairs New Jersey Health Care Center for the study.
Methods
A retrospective chart review was conducted on veterans evaluated at the WRIISC from March 1, 2015, to January 31, 2019. Inclusion criteria were: deployment to operations Desert Shield and Desert Storm between August 2, 1990, and February 28, 1991, and skin biopsy conducted at the WRIISC. Skin biopsies were obtained at the discretion of an examining clinician based on clinical indications, including neuropathic pain, ANS symptoms, and/or a fibromyalgia/chronic pain–type presentation.
Electronic health record review explicitly abstracted GWI status, results of the skin biopsy, and ANS symptom burden as determined by the Composite Autonomic Symptom Scale 31 (COMPASS 31) completed at the time of the WRIISC evaluation.
COMPASS 31 assesses symptoms across 6 domains (orthostatic, vasomotor, secretomotor, gastrointestinal, bladder, andpupillomotor). Patients are asked about symptom frequency (rarely to almost always), severity (mild to severe), and improvement (much worse to completely gone). Individual domain scores and a total weighted score (0-100) have demonstrated good validity, reliability, and consistency in SFN.33,34
In veterans with GWI and documented SFN, a health record review was performed to identify potential etiologies for SFN (Appendix).
Statistical Analysis
Microsoft Excel and IBM SPSS 12.0.1 for Windows were used for data collection and statistical analysis. Fisher exact test was used for comparing the prevalence of SFN in veterans with GWI vs without GWI. The independent samples t test was used for comparing COMPASS 31 scores for veterans with GWI by SFN status. α < .05 was used for determining statistical significance. For those GWVs documented with SFN and GWI, potential explanations were documented in total and by condition.
Results
From March 1, 2015, to January 31, 2019, 141 GWVs received a comprehensive in person clinical evaluation at the WRIISC and 51 veterans (36%) received a skin biopsy and were included in this retrospective observational study (Figure). The mean age was 48.6 years, and the majority were male and served in the US Army. Skin biopsies met clinical criteria for GWI for 42 (82%) and 24 of 42 (57%) were determined to have SFN. Four of 9 (44%) veterans without GWI had positive SFN biopsies, though this difference was not statistically significant (Table 1). Veterans with SFN but no GWI were not included in the further analysis.
Thirty-five veterans with GWI—18 with SFN and 17 without SFN—completed the COMPASS 31 (Table 2). COMPASS 31 data were not analyzed for veterans without GWI. Individual domain scores and the difference in COMPASS 31 scores for veterans with GWI and SFN vs GWI and no SFN (38.3 vs 37.8, respectively) were not statistically significant.
Sixteen of 24 veterans with GWI and SFN (67%) had ≥ 1 conditions that could potentially be responsible for SFN (Table 3), including 11 veterans (46%) with prediabetes/diabetes. Hyperlipidemia is only variably reported as a cause of SFN; when included, 19 of 24 (79%) SFN cases were accounted for. We could not identify a medical explanation for SFN in 5 of 24 veterans (21%) with GWI, which were deemed to be idiopathic.
Discussion
Biopsy-confirmed SFN was present in more than half of our sample of veterans with GWI, which is broadly consistent with what has been reported in the literature.13,35-38 In this clinical observation study, SFN was similarly prevalent in veterans with and without GWI; although it should be noted that biopsies only were obtained when there was a strong clinical suspicion for SFN. Almost half of patients with GWI did not have SFN, so our study does not support SFN as the underlying explanation for all GWI. Although our data cannot provide clinical guidance as to when skin biopsy may be indicated in GWI, work done in fibromyalgia found symptoms of dysautonomia and paresthesias are more specific for SFN and may be useful to help guide medical decision making.39
Veterans with GWI in our clinical sample reported a high burden of clinical symptoms conceivably attributable to ANS dysfunction. This symptom reporting is consistent with that seen in other GWI studies, as well as in other studies of SFN.4,5,7-9,14,15,34,38,40 Our clinical sample of veterans with GWI found no differences in the ANS symptom reporting between those with and without SFN. Therefore, our study cannot support SFN alone as accounting for ANS symptom burden in patients with GWI.
Two-thirds of biopsy-confirmed SFN in our clinical sample of veterans with GWI could potentially be explained by established medical conditions. As in other studies of SFN, prediabetes and diabetes represented a plurality (46%). Even after considering hyperlipidemia as a potential explanation, about 21% of SFN cases in veterans with GWI still were deemed idiopathic.
Evidence supports certain environmental agents as causal factors for GWI. Neurotoxicants reportedly related to GWI include pesticides (particularly organophosphates and carbamates), pyridostigmine bromide (used during the Gulf War as a prophylactic agent against the use of chemical weapons), and low levels of the nerve agent sarin from environmental contamination due to chemical weapons detonations.1 Some of these agents have been implicated in neuropathy as well.1,28-30 It is biologically plausible that deployment-related exposures could trigger SFN, though the traditional consensus has been that remote exposure to neurotoxic substances is unlikely to produce neuropathy that presents many years after the exposure.41 In the WRIISC clinical experience, however, veterans often report that their neuropathic symptoms predate the diagnosis of the associated medical conditions, sometimes by decades. It is conceivable that remote exposures may trigger the condition that is then potentiated by ongoing exposures, metabolic factors, and/or other medical conditions. These may perpetuate neuropathic symptoms and the illness experience of affected veterans. Our clinical observation study cannot clarify the extent to which this may be the case. Despite these findings and arguments, an environmental contribution to SFN cannot be discounted, and further research is needed to explore a potential relationship.
Limitations
This study’s conclusions are limited by its observational/retrospective design in a relatively small clinical sample of veterans evaluated at a tertiary referral center for postdeployment exposure-related health concerns. The WRIISC clinical sample is not representative of all GWVs or even of all veterans with GWI, as there is inherent selection bias as to who gets referred to and evaluated at the WRIISC. As with studies based on retrospective chart review, data are reliant on clinical documentation andaccuracy/consistency of the reviewer. Evaluation for SFN with skin biopsy is an invasive procedure and was performed when a high index of clinical suspicion for this condition existed, possibly representing confirmation bias. Therefore, the relatively high prevalence ofbiopsy-confirmed SFN seen in our clinical sample cannot be generalized to GWVs as a whole or even to veterans with GWI.
Assessment of autonomic dysfunction was based on COMPASS 31 symptom reporting by an small subset of the clinical cohort. Symptom reporting may not be reflective of true abnormality in ANS function. Physiologic tests of the ANS were not performed; such studies could more objectively establish whether ANS dysfunction is more prevalent in GWI veterans with SFN.
Evaluation for all potential etiologic/contributory conditions to SFN was not exhaustive. For example, sodium channel gene mutations have been documented to account for up to one-third of all cases of idiopathic SFN.42 For those cases in which no compelling etiology was identified, it is plausible that medical explanations for SFN may be found on further investigation.
Clinical assessments at the WRIISC were performed on GWVs ≥ 26 years after their deployment-related exposures. Other conditions/exposures may have occurred in the interim. What is not clear is whether the SFN predated the onset of any of these medical conditions or other putative contributors. This observational study is not able to tease out a temporal association to make a cause-and-effect assessment.
Conclusions
Retrospective analysis of clinical data of veterans evaluated at a specialized center for postdeployment health demonstrated that skin biopsy–confirmed SFN was prevalent, but not ubiquitous, in veterans with GWI. Symptom that may be attributed to ANS dysfunction in this clinical sample was consistent with literature on SFN and with GWI, but we could not definitively attribute ANS symptoms to SFN. Our study does not support the hypothesis that GWI symptoms are solely due to SFN, though it may still be relevant in a subset of veterans with GWI with strongly suggestive clinical features. We were able to identify a potential etiology for SFN in most veterans with GWI. Further investigations are recommended to explore any potential relationship between Gulf War exposures and SFN.
1. White RF, Steele L, O’Callaghan JP, et al. Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: effects of toxicant exposures during deployment. Cortex. 2016;74:449-475. doi:10.1016/j.cortex.2015.08.022
2. Committee on the Development of a Consensus Case Definition for Chronic Multisymptom Illness in 1990-1991 Gulf War Veterans, Board on the Health of Select Populations, Institute of Medicine. Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined. National Academies Press; 2014.
3. Robbins R, Helmer D, Monahan P, et al. Management of chronic multisymptom illness: synopsis of the 2021 US Department of Veterans Affairs and US Department of Defense Clinical Practice Guideline. Mayo Clin Proc. 2022;97(5):991-1002. doi:10.1016/j.mayocp.2022.01.031
4. Fox A, Helmer D, Tseng CL, Patrick-DeLuca L, Osinubi O. Report of autonomic symptoms in a clinical sample of veterans with Gulf War Illness. Mil Med. 2018;183(3-4):e179-e185. doi:10.1093/milmed/usx052
5. Fox A, Helmer D, Tseng CL, McCarron K, Satcher S, Osinubi O. Autonomic symptoms in Gulf War veterans evaluated at the War Related Illness and Injury Study Center. Mil Med. 2019;184(3-4):e191-e196. doi:10.1093/milmed/usy227
6. Reyes L, Falvo M, Blatt M, Ghobreal B, Acosta A, Serrador J. Autonomic dysfunction in veterans with Gulf War illness [abstract]. FASEB J. 2014;28(S1):1068.19. doi:10.1096/fasebj.28.1_supplement.1068.19
7. Haley RW, Charuvastra E, Shell WE, et al. Cholinergic autonomic dysfunction in veterans with Gulf War illness: confirmation in a population-based sample. JAMA Neurol. 2013;70(2):191-200. doi:10.1001/jamaneurol.2013.596
8. Haley RW, Vongpatanasin W, Wolfe GI, et al. Blunted circadian variation in autonomic regulation of sinus node function in veterans with Gulf War syndrome. Am J Med. 2004;117(7):469-478. doi:10.1016/j.amjmed.2004.03.041
9. Avery TJ, Mathersul DC, Schulz-Heik RJ, Mahoney L, Bayley PJ. Self-reported autonomic dysregulation in Gulf War Illness. Mil Med. Published online December 30, 2021. doi:10.1093/milmed/usab546
10. Verne ZT, Fields JZ, Zhang BB, Zhou Q. Autonomic dysfunction and gastroparesis in Gulf War veterans. J Investig Med. 2023;71(1):7-10. doi:10.1136/jim-2021-002291
11. Levine TD. Small fiber neuropathy: disease classification beyond pain and burning. J Cent Nerv Syst Dis. 2018;10:1179573518771703. doi:10.1177/1179573518771703
12. Novak P. Autonomic disorders. Am J Med. 2019;132(4):420-436. doi:10.1016/j.amjmed.2018.09.027
13. Oaklander AL, Klein MM. Undiagnosed small-fiber polyneuropathy: is it a component of Gulf War Illness? Defense Technical Information Center. Accessed February 21, 2024. https://apps.dtic.mil/sti/citations/ADA613891
14. Sène D. Small fiber neuropathy: diagnosis, causes, and treatment. Joint Bone Spine. 2018;85(5):553-559. doi:10.1016/j.jbspin.2017.11.002
15. Novak V, Freimer ML, Kissel JT, et al. Autonomic impairment in painful neuropathy. Neurology. 2001;56(7):861-868. doi:10.1212/wnl.56.7.861
16. Myers MI, Peltier AC. Uses of skin biopsy for sensory and autonomic nerve assessment. Curr Neurol Neurosci Rep. 2013;13(1):323. doi:10.1007/s11910-012-0323-2
17. Haroutounian S, Todorovic MS, Leinders M, et al. Diagnostic criteria for idiopathic small fiber neuropathy: a systematic review. Muscle Nerve. 2021;63(2):170-177. doi:10.1002/mus.27070
18. Levine TD, Saperstein DS. Routine use of punch biopsy to diagnose small fiber neuropathy in fibromyalgia patients. Clin Rheumatol. 2015;34(3):413-417. doi:10.1007/s10067-014-2850-5
19. England JD, Gronseth G S, Franklin G, et al. Practice parameter: the evaluation of distal symmetric polyneuropathy: the role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. PM R. 2009;1(1):14-22. doi:10.1016/j.pmrj.2008.11.011
20. de Greef BTA, Hoeijmakers JGJ, Gorissen-Brouwers CML, Geerts M, Faber CG, Merkies ISJ. Associated conditions in small fiber neuropathy - a large cohort study and review of the literature. Eur J Neurol. 2018;25(2):348-355. doi:10.1111/ene.13508
21. Morkavuk G, Leventoglu A. Small fiber neuropathy associated with hyperlipidemia: utility of cutaneous silent periods and autonomic tests. ISRN Neurol. 2014;2014:579242. doi:10.1155/2014/579242
22. Bednarik J, Vlckova-Moravcova E, Bursova S, Belobradkova J, Dusek L, Sommer C. Etiology of small-fiber neuropathy. J Peripher Nerv Syst. 2009;14(3):177-183. doi:10.1111/j.1529-8027.2009.00229.x
23. Kokotis P, Papantoniou M, Schmelz M, Buntziouka C, Tzavellas E, Paparrigopoulos T. Pure small fiber neuropathy in alcohol dependency detected by skin biopsy. Alcohol Fayettev N. 2023;111:67-73. doi:10.1016/j.alcohol.2023.05.006
24. Guimarães-Costa R, Schoindre Y, Metlaine A, et al. N-hexane exposure: a cause of small fiber neuropathy. J Peripher Nerv Syst. 2018;23(2):143-146. doi:10.1111/jns.12261
25. Koszewicz M, Markowska K, Waliszewska-Prosol M, et al. The impact of chronic co-exposure to different heavy metals on small fibers of peripheral nerves. A study of metal industry workers. J Occup Med Toxicol. 2021;16(1):12. doi:10.1186/s12995-021-00302-6
26. Johns Hopkins Medicine. Small nerve fibers defy neuropathy conventions. April 11, 2016. Accessed February 21, 2024. https://www.hopkinsmedicine.org/news/media/releases/small_nerve_fibers_defy_neuropathy_conventions
27. Jett DA. Neurotoxic pesticides and neurologic effects. Neurol Clin. 2011;29(3):667-677. doi:10.1016/j.ncl.2011.06.002
28. Berger AR, Schaumburg HH. Human toxic neuropathy caused by industrial agents. In: Dyck PJ, Thomas PK, eds. Peripheral Neuropathy. 4th ed. Saunders; 2005:2505-2525. doi:10.1016/B978-0-7216-9491-7.50115-0
29. Herskovitz S, Schaumburg HH. Neuropathy caused by drugs. In: Dyck PJ, Thomas PK, eds. Peripheral Neuropathy. 4th ed. Saunders; 2005:2553-2583.
30. Katona I, Weis J. Chapter 31 - Diseases of the peripheral nerves. Handb Clin Neurol. 2017;145:453-474. doi:10.1016/B978-0-12-802395-2.00031-6
31. Matikainen E, Juntunen J. Autonomic nervous system dysfunction in workers exposed to organic solvents. J Neurol Neurosurg Psychiatry. 1985;48(10):1021-1024. doi:10.1136/jnnp.48.10.1021
32. Murata K, Araki S, Yokoyama K, Maeda K. Autonomic and peripheral nervous system dysfunction in workers exposed to mixed organic solvents. Int Arch Occup Environ Health. 1991;63(5):335-340. doi:10.1007/BF00381584
33. Sletten DM, Suarez GA, Low PA, Mandrekar J, Singer W. COMPASS 31: a refined and abbreviated Composite Autonomic Symptom Score. Mayo Clin Proc. 2012;87(12):1196-1201. doi:10.1016/j.mayocp.2012.10.013
34. Treister R, O’Neil K, Downs HM, Oaklander AL. Validation of the Composite Autonomic Symptom Scale-31 (COMPASS-31) in patients with and without small-fiber polyneuropathy. Eur J Neurol. 2015;22(7):1124-1130. doi:10.1111/ene.12717
35. Joseph P, Arevalo C, Oliveira RKF, et al. Insights from invasive cardiopulmonary exercise testing of patients with myalgic encephalomyelitis/chronic fatigue syndrome. Chest. 2021;160(2):642-651. doi:10.1016/j.chest.2021.01.082
36. Giannoccaro MP, Donadio V, Incensi A, Avoni P, Liguori R. Small nerve fiber involvement in patients referred for fibromyalgia. Muscle Nerve. 2014;49(5):757-759. doi:10.1002/mus.24156
37. Oaklander AL, Herzog ZD, Downs HM, Klein MM. Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain. 2013;154(11):2310-2316. doi:10.1016/j.pain.2013.06.001
38. Serrador JM. Diagnosis of late-stage, early-onset, small-fiber polyneuropathy. Defense Technical Information Center. December 1, 2019. Accessed February 21, 2024. https://apps.dtic.mil/sti/citations/AD1094831
39. Lodahl M, Treister R, Oaklander AL. Specific symptoms may discriminate between fibromyalgia patients with vs without objective test evidence of small-fiber polyneuropathy. Pain Rep. 2018;3(1):e633. doi:10.1097/PR9.0000000000000633
40. Sastre A, Cook MR. Autonomic dysfunction in Gulf War veterans. Defense Technical Information Center. April 1, 2004. Accessed February 21, 2024. https://apps.dtic.mil/sti/citations/ADA429525
41. Little AA, Albers JW. Clinical description of toxic neuropathies. Handb Clin Neurol. 2015;131:253-296. doi:10.1016/B978-0-444-62627-1.00015-9
42. Faber CG, Hoeijmakers JGJ, Ahn HS, et al. Gain of function NaV1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol. 2012;71(1):26-39.
1. White RF, Steele L, O’Callaghan JP, et al. Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: effects of toxicant exposures during deployment. Cortex. 2016;74:449-475. doi:10.1016/j.cortex.2015.08.022
2. Committee on the Development of a Consensus Case Definition for Chronic Multisymptom Illness in 1990-1991 Gulf War Veterans, Board on the Health of Select Populations, Institute of Medicine. Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined. National Academies Press; 2014.
3. Robbins R, Helmer D, Monahan P, et al. Management of chronic multisymptom illness: synopsis of the 2021 US Department of Veterans Affairs and US Department of Defense Clinical Practice Guideline. Mayo Clin Proc. 2022;97(5):991-1002. doi:10.1016/j.mayocp.2022.01.031
4. Fox A, Helmer D, Tseng CL, Patrick-DeLuca L, Osinubi O. Report of autonomic symptoms in a clinical sample of veterans with Gulf War Illness. Mil Med. 2018;183(3-4):e179-e185. doi:10.1093/milmed/usx052
5. Fox A, Helmer D, Tseng CL, McCarron K, Satcher S, Osinubi O. Autonomic symptoms in Gulf War veterans evaluated at the War Related Illness and Injury Study Center. Mil Med. 2019;184(3-4):e191-e196. doi:10.1093/milmed/usy227
6. Reyes L, Falvo M, Blatt M, Ghobreal B, Acosta A, Serrador J. Autonomic dysfunction in veterans with Gulf War illness [abstract]. FASEB J. 2014;28(S1):1068.19. doi:10.1096/fasebj.28.1_supplement.1068.19
7. Haley RW, Charuvastra E, Shell WE, et al. Cholinergic autonomic dysfunction in veterans with Gulf War illness: confirmation in a population-based sample. JAMA Neurol. 2013;70(2):191-200. doi:10.1001/jamaneurol.2013.596
8. Haley RW, Vongpatanasin W, Wolfe GI, et al. Blunted circadian variation in autonomic regulation of sinus node function in veterans with Gulf War syndrome. Am J Med. 2004;117(7):469-478. doi:10.1016/j.amjmed.2004.03.041
9. Avery TJ, Mathersul DC, Schulz-Heik RJ, Mahoney L, Bayley PJ. Self-reported autonomic dysregulation in Gulf War Illness. Mil Med. Published online December 30, 2021. doi:10.1093/milmed/usab546
10. Verne ZT, Fields JZ, Zhang BB, Zhou Q. Autonomic dysfunction and gastroparesis in Gulf War veterans. J Investig Med. 2023;71(1):7-10. doi:10.1136/jim-2021-002291
11. Levine TD. Small fiber neuropathy: disease classification beyond pain and burning. J Cent Nerv Syst Dis. 2018;10:1179573518771703. doi:10.1177/1179573518771703
12. Novak P. Autonomic disorders. Am J Med. 2019;132(4):420-436. doi:10.1016/j.amjmed.2018.09.027
13. Oaklander AL, Klein MM. Undiagnosed small-fiber polyneuropathy: is it a component of Gulf War Illness? Defense Technical Information Center. Accessed February 21, 2024. https://apps.dtic.mil/sti/citations/ADA613891
14. Sène D. Small fiber neuropathy: diagnosis, causes, and treatment. Joint Bone Spine. 2018;85(5):553-559. doi:10.1016/j.jbspin.2017.11.002
15. Novak V, Freimer ML, Kissel JT, et al. Autonomic impairment in painful neuropathy. Neurology. 2001;56(7):861-868. doi:10.1212/wnl.56.7.861
16. Myers MI, Peltier AC. Uses of skin biopsy for sensory and autonomic nerve assessment. Curr Neurol Neurosci Rep. 2013;13(1):323. doi:10.1007/s11910-012-0323-2
17. Haroutounian S, Todorovic MS, Leinders M, et al. Diagnostic criteria for idiopathic small fiber neuropathy: a systematic review. Muscle Nerve. 2021;63(2):170-177. doi:10.1002/mus.27070
18. Levine TD, Saperstein DS. Routine use of punch biopsy to diagnose small fiber neuropathy in fibromyalgia patients. Clin Rheumatol. 2015;34(3):413-417. doi:10.1007/s10067-014-2850-5
19. England JD, Gronseth G S, Franklin G, et al. Practice parameter: the evaluation of distal symmetric polyneuropathy: the role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. PM R. 2009;1(1):14-22. doi:10.1016/j.pmrj.2008.11.011
20. de Greef BTA, Hoeijmakers JGJ, Gorissen-Brouwers CML, Geerts M, Faber CG, Merkies ISJ. Associated conditions in small fiber neuropathy - a large cohort study and review of the literature. Eur J Neurol. 2018;25(2):348-355. doi:10.1111/ene.13508
21. Morkavuk G, Leventoglu A. Small fiber neuropathy associated with hyperlipidemia: utility of cutaneous silent periods and autonomic tests. ISRN Neurol. 2014;2014:579242. doi:10.1155/2014/579242
22. Bednarik J, Vlckova-Moravcova E, Bursova S, Belobradkova J, Dusek L, Sommer C. Etiology of small-fiber neuropathy. J Peripher Nerv Syst. 2009;14(3):177-183. doi:10.1111/j.1529-8027.2009.00229.x
23. Kokotis P, Papantoniou M, Schmelz M, Buntziouka C, Tzavellas E, Paparrigopoulos T. Pure small fiber neuropathy in alcohol dependency detected by skin biopsy. Alcohol Fayettev N. 2023;111:67-73. doi:10.1016/j.alcohol.2023.05.006
24. Guimarães-Costa R, Schoindre Y, Metlaine A, et al. N-hexane exposure: a cause of small fiber neuropathy. J Peripher Nerv Syst. 2018;23(2):143-146. doi:10.1111/jns.12261
25. Koszewicz M, Markowska K, Waliszewska-Prosol M, et al. The impact of chronic co-exposure to different heavy metals on small fibers of peripheral nerves. A study of metal industry workers. J Occup Med Toxicol. 2021;16(1):12. doi:10.1186/s12995-021-00302-6
26. Johns Hopkins Medicine. Small nerve fibers defy neuropathy conventions. April 11, 2016. Accessed February 21, 2024. https://www.hopkinsmedicine.org/news/media/releases/small_nerve_fibers_defy_neuropathy_conventions
27. Jett DA. Neurotoxic pesticides and neurologic effects. Neurol Clin. 2011;29(3):667-677. doi:10.1016/j.ncl.2011.06.002
28. Berger AR, Schaumburg HH. Human toxic neuropathy caused by industrial agents. In: Dyck PJ, Thomas PK, eds. Peripheral Neuropathy. 4th ed. Saunders; 2005:2505-2525. doi:10.1016/B978-0-7216-9491-7.50115-0
29. Herskovitz S, Schaumburg HH. Neuropathy caused by drugs. In: Dyck PJ, Thomas PK, eds. Peripheral Neuropathy. 4th ed. Saunders; 2005:2553-2583.
30. Katona I, Weis J. Chapter 31 - Diseases of the peripheral nerves. Handb Clin Neurol. 2017;145:453-474. doi:10.1016/B978-0-12-802395-2.00031-6
31. Matikainen E, Juntunen J. Autonomic nervous system dysfunction in workers exposed to organic solvents. J Neurol Neurosurg Psychiatry. 1985;48(10):1021-1024. doi:10.1136/jnnp.48.10.1021
32. Murata K, Araki S, Yokoyama K, Maeda K. Autonomic and peripheral nervous system dysfunction in workers exposed to mixed organic solvents. Int Arch Occup Environ Health. 1991;63(5):335-340. doi:10.1007/BF00381584
33. Sletten DM, Suarez GA, Low PA, Mandrekar J, Singer W. COMPASS 31: a refined and abbreviated Composite Autonomic Symptom Score. Mayo Clin Proc. 2012;87(12):1196-1201. doi:10.1016/j.mayocp.2012.10.013
34. Treister R, O’Neil K, Downs HM, Oaklander AL. Validation of the Composite Autonomic Symptom Scale-31 (COMPASS-31) in patients with and without small-fiber polyneuropathy. Eur J Neurol. 2015;22(7):1124-1130. doi:10.1111/ene.12717
35. Joseph P, Arevalo C, Oliveira RKF, et al. Insights from invasive cardiopulmonary exercise testing of patients with myalgic encephalomyelitis/chronic fatigue syndrome. Chest. 2021;160(2):642-651. doi:10.1016/j.chest.2021.01.082
36. Giannoccaro MP, Donadio V, Incensi A, Avoni P, Liguori R. Small nerve fiber involvement in patients referred for fibromyalgia. Muscle Nerve. 2014;49(5):757-759. doi:10.1002/mus.24156
37. Oaklander AL, Herzog ZD, Downs HM, Klein MM. Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain. 2013;154(11):2310-2316. doi:10.1016/j.pain.2013.06.001
38. Serrador JM. Diagnosis of late-stage, early-onset, small-fiber polyneuropathy. Defense Technical Information Center. December 1, 2019. Accessed February 21, 2024. https://apps.dtic.mil/sti/citations/AD1094831
39. Lodahl M, Treister R, Oaklander AL. Specific symptoms may discriminate between fibromyalgia patients with vs without objective test evidence of small-fiber polyneuropathy. Pain Rep. 2018;3(1):e633. doi:10.1097/PR9.0000000000000633
40. Sastre A, Cook MR. Autonomic dysfunction in Gulf War veterans. Defense Technical Information Center. April 1, 2004. Accessed February 21, 2024. https://apps.dtic.mil/sti/citations/ADA429525
41. Little AA, Albers JW. Clinical description of toxic neuropathies. Handb Clin Neurol. 2015;131:253-296. doi:10.1016/B978-0-444-62627-1.00015-9
42. Faber CG, Hoeijmakers JGJ, Ahn HS, et al. Gain of function NaV1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol. 2012;71(1):26-39.
Hereditary Amyloidosis: 5 Things to Know
Amyloidosis is a condition marked by the accumulation of insoluble beta-sheet fibrillar protein aggregates in tissues that can be acquired or hereditary. Hereditary amyloidogenic transthyretin (hATTR) amyloidosis is an autosomal-dominant disease caused by pathogenic variants in the TTR gene. The TTR protein is essential for transporting thyroxine and retinol-binding protein and is primarily synthesized in the liver, becoming unstable as a result of the pathogenic mutations. Inherited pathogenic variants lead to the protein’s misfolding, aggregation, and deposition as amyloid fibrils in different organs, resulting in progressive multisystem dysfunction. hATTR amyloidosis is a heterogenous disease, characterized by a wide range of clinical manifestations affecting the peripheral (both somatic and autonomic) nervous system, heart, kidneys, and central nervous system (CNS); however, the heart and peripheral nerves appear to be the main targets of the TTR-related pathologic process. Without treatment, the prognosis is poor, with an average life expectancy of 7-11 years; however, in recent years, the development of new therapeutics has brought new hope to patients.
Here are five things to know about hereditary amyloidosis.
1. Diagnosis of hereditary amyloidosis requires a high level of suspicion.
The diagnosis of hATTR amyloidosis presents a significant challenge, particularly in nonendemic regions where a lack of family history and heterogeneity of clinical presentation can delay diagnosis by 4-5 years. A timely diagnosis requires clinicians to maintain a high index of suspicion, especially when evaluating patients with neuropathic symptoms. Early diagnosis is crucial to begin patients on recently available disease-modifying therapies that can slow the disease course. Failure to recognize is the major barrier to improved patient outcomes.
Confirming the diagnosis involves detecting amyloid deposits in tissue biopsy specimens from various possible sites, including the skin, nerves, myocardium, and others. However, the diagnosis can be challenging owing to the uneven distribution of amyloid fibrils, sometimes requiring multiple biopsies or alternative diagnostic approaches, such as TTR gene sequencing, to confirm the presence of an amyloidogenic pathogenic variant. Biopsy for hATTR amyloidosis is not required if imaging of the clinical phenotype and genetic testing are consistent.
Once diagnosed, the assessment of organ involvement is essential, using nerve conduction studies, cardiac investigations (eg, echocardiography, ECG, scintigraphy), ophthalmologic assessments, and complete renal function evaluations to fully understand the extent of disease impact.
2. Hereditary amyloidosis diseases are classified into two primary categories.
Hereditary amyloidosis represents a group of diseases caused by inherited gene mutations and is classified into two main types: ATTR (transthyretin-related) and non-TTR. Most cases of hereditary amyloidosis are associated with the TTR gene. Mutations in this protein lead to different forms of ATTR amyloidosis, categorized on the basis of the specific mutation involved, such as hATTR50M (genotype Val50Met), which is the most prevalent form.
ATTR mutations result in a variety of health issues, manifesting in three primary forms:
- Neuropathic ATTR (genotype Val50Met): Early symptoms include sensorimotor polyneuropathy of the legs, carpal tunnel syndrome, autonomic dysfunction, constipation/diarrhea, and impotence; late symptoms include cardiomyopathy, vitreous opacities, glaucoma, nephropathy, and CNS symptoms.
- Cardiac ATTR (genotype Val142Ile): This type is characterized by cardiomegaly, conduction block, arrhythmia, anginal pain, congestive heart failure, and sudden death.
- Leptomeningeal ATTR (genotype Asp38Gly): This is characterized by transient focal neurologic episodes, intracerebral and/or subarachnoid hemorrhages, dementia, ataxia, and psychosis.
Non-TTR amyloidoses are rarer than are ATTR variations and involve mutations in different genes that also have significant health impacts. These include proteins such as apolipoprotein AI, fibrinogen A alpha, lysozyme, apolipoprotein AII, gelsolin, and cystatin C. Each type contributes to a range of symptoms and requires individualized management approaches.
3. Heightened disease awareness has increased the recognized prevalence of hereditary amyloidosis.
hATTR amyloidosis has historically been recognized as a rare disease, with significant clusters in Portugal, Brazil, Sweden, and Japan and alongside smaller foci in regions such as Cyprus and Majorca. This disease›s variable incidence across Europe is now perceived to be on the rise. It is attributed to heightened disease awareness among healthcare providers and the broader availability of genetic testing, extending its recognized impact to at least 29 countries globally. The genetic landscape of hATTR amyloidosis is diverse, with over 140 mutations identified in the TTR gene. Among these, the Val50Met mutation is particularly notable for its association with large patient clusters in the endemic regions.
Morbidity and mortality associated with hATTR amyloidosis are significant, with an average lifespan of 7-11 years post diagnosis; however, survival rates can vary widely depending on the specific genetic variant and organ involvement. Early diagnosis can substantially improve outcomes; yet, for many, the prognosis remains poor, especially in cases dominated by cardiomyopathy. Genetics play a central role in the disease›s transmission, with autosomal-dominant inheritance patterns and high penetrance among carriers of pathogenic mutations. Research continues to uncover the broad spectrum of genetic variations contributing to hATTR amyloidosis, with ongoing studies poised to expand our understanding of its molecular underpinnings and potential treatment options.
4. The effect on quality of life is significant both in patients living with hATTR amyloidosis and their caregivers.
hATTR amyloidosis imposes a multifaceted burden on patients and their caregivers as the disease progresses. Symptoms range from sensorimotor impairment and gastrointestinal or autonomic dysfunction to heart failure, leading to significant health-related quality-of-life deficits. The systemic nature of hATTR amyloidosis significantly affects patients› lifestyles, daily activities, and general well-being, especially because it typically manifests in adulthood — a crucial time for occupational changes. The progression of hATTR amyloidosis exacerbates the challenges in maintaining employment and managing household chores, with symptomatic patients often unable to work and experiencing difficulties with absenteeism and presenteeism when they are able to work.
hATTR amyloidosis leads to physical, mental, occupational, and social limitations for patients, and it also places a considerable strain on their families and caregivers, who report poor mental health, work impairment, and a high time commitment (mean, 45.9 h/wk) to providing care.
5. There have been significant advancements in therapeutic options for early-stage hATTR amyloidosis.
After diagnosis, prompt initiation of treatment is recommended to delay the progression of hATTR amyloidosis; a multidisciplinary approach is essential, incorporating anti-amyloid therapy to inhibit further production and/or deposition of amyloid aggregates. Treatment strategies also include addressing symptomatic therapy and managing cardiac, renal, and ocular involvement. Although many therapies have been developed, especially for the early stages of hATTR amyloidosis, therapeutic benefits for patients with advanced disease remain limited.
Recent advancements in the treatment of hATTR amyloidosis have introduced RNA-targeted therapies including patisiran, vutrisiran, and eplontersen, which have shown efficacy in reducing hepatic TTR synthesis and the aggregation of misfolded monomers into amyloid deposits. These therapies, ranging from small interfering RNA formulations to antisense oligonucleotides, offer benefits in managing both cardiomyopathy and neuropathy associated with hATTR amyloidosis , administered through various methods, including intravenous infusions and subcutaneous injections. In addition, the stabilization of TTR tetramers with the use of drugs such as tafamidis and diflunisal has effectively prevented the formation of amyloidogenic monomers. Moreover, other investigational agents, including TTR stabilizers like acoramidis and tolcapone, as well as novel compounds that inhibit amyloid formation and disrupt fibrils, are expanding the therapeutic landscape for hATTR amyloidosis , providing hope for improved management of this complex condition.
Dr. Gertz is a professor and consultant in the Department of Hematology, Mayo Clinic, Rochester, Minnesota. He has disclosed the following relevant financial relationships: Received income in an amount equal to or greater than $250 from AstraZeneca, Ionis, and Alnylym.
A version of this article appeared on Medscape.com.
Amyloidosis is a condition marked by the accumulation of insoluble beta-sheet fibrillar protein aggregates in tissues that can be acquired or hereditary. Hereditary amyloidogenic transthyretin (hATTR) amyloidosis is an autosomal-dominant disease caused by pathogenic variants in the TTR gene. The TTR protein is essential for transporting thyroxine and retinol-binding protein and is primarily synthesized in the liver, becoming unstable as a result of the pathogenic mutations. Inherited pathogenic variants lead to the protein’s misfolding, aggregation, and deposition as amyloid fibrils in different organs, resulting in progressive multisystem dysfunction. hATTR amyloidosis is a heterogenous disease, characterized by a wide range of clinical manifestations affecting the peripheral (both somatic and autonomic) nervous system, heart, kidneys, and central nervous system (CNS); however, the heart and peripheral nerves appear to be the main targets of the TTR-related pathologic process. Without treatment, the prognosis is poor, with an average life expectancy of 7-11 years; however, in recent years, the development of new therapeutics has brought new hope to patients.
Here are five things to know about hereditary amyloidosis.
1. Diagnosis of hereditary amyloidosis requires a high level of suspicion.
The diagnosis of hATTR amyloidosis presents a significant challenge, particularly in nonendemic regions where a lack of family history and heterogeneity of clinical presentation can delay diagnosis by 4-5 years. A timely diagnosis requires clinicians to maintain a high index of suspicion, especially when evaluating patients with neuropathic symptoms. Early diagnosis is crucial to begin patients on recently available disease-modifying therapies that can slow the disease course. Failure to recognize is the major barrier to improved patient outcomes.
Confirming the diagnosis involves detecting amyloid deposits in tissue biopsy specimens from various possible sites, including the skin, nerves, myocardium, and others. However, the diagnosis can be challenging owing to the uneven distribution of amyloid fibrils, sometimes requiring multiple biopsies or alternative diagnostic approaches, such as TTR gene sequencing, to confirm the presence of an amyloidogenic pathogenic variant. Biopsy for hATTR amyloidosis is not required if imaging of the clinical phenotype and genetic testing are consistent.
Once diagnosed, the assessment of organ involvement is essential, using nerve conduction studies, cardiac investigations (eg, echocardiography, ECG, scintigraphy), ophthalmologic assessments, and complete renal function evaluations to fully understand the extent of disease impact.
2. Hereditary amyloidosis diseases are classified into two primary categories.
Hereditary amyloidosis represents a group of diseases caused by inherited gene mutations and is classified into two main types: ATTR (transthyretin-related) and non-TTR. Most cases of hereditary amyloidosis are associated with the TTR gene. Mutations in this protein lead to different forms of ATTR amyloidosis, categorized on the basis of the specific mutation involved, such as hATTR50M (genotype Val50Met), which is the most prevalent form.
ATTR mutations result in a variety of health issues, manifesting in three primary forms:
- Neuropathic ATTR (genotype Val50Met): Early symptoms include sensorimotor polyneuropathy of the legs, carpal tunnel syndrome, autonomic dysfunction, constipation/diarrhea, and impotence; late symptoms include cardiomyopathy, vitreous opacities, glaucoma, nephropathy, and CNS symptoms.
- Cardiac ATTR (genotype Val142Ile): This type is characterized by cardiomegaly, conduction block, arrhythmia, anginal pain, congestive heart failure, and sudden death.
- Leptomeningeal ATTR (genotype Asp38Gly): This is characterized by transient focal neurologic episodes, intracerebral and/or subarachnoid hemorrhages, dementia, ataxia, and psychosis.
Non-TTR amyloidoses are rarer than are ATTR variations and involve mutations in different genes that also have significant health impacts. These include proteins such as apolipoprotein AI, fibrinogen A alpha, lysozyme, apolipoprotein AII, gelsolin, and cystatin C. Each type contributes to a range of symptoms and requires individualized management approaches.
3. Heightened disease awareness has increased the recognized prevalence of hereditary amyloidosis.
hATTR amyloidosis has historically been recognized as a rare disease, with significant clusters in Portugal, Brazil, Sweden, and Japan and alongside smaller foci in regions such as Cyprus and Majorca. This disease›s variable incidence across Europe is now perceived to be on the rise. It is attributed to heightened disease awareness among healthcare providers and the broader availability of genetic testing, extending its recognized impact to at least 29 countries globally. The genetic landscape of hATTR amyloidosis is diverse, with over 140 mutations identified in the TTR gene. Among these, the Val50Met mutation is particularly notable for its association with large patient clusters in the endemic regions.
Morbidity and mortality associated with hATTR amyloidosis are significant, with an average lifespan of 7-11 years post diagnosis; however, survival rates can vary widely depending on the specific genetic variant and organ involvement. Early diagnosis can substantially improve outcomes; yet, for many, the prognosis remains poor, especially in cases dominated by cardiomyopathy. Genetics play a central role in the disease›s transmission, with autosomal-dominant inheritance patterns and high penetrance among carriers of pathogenic mutations. Research continues to uncover the broad spectrum of genetic variations contributing to hATTR amyloidosis, with ongoing studies poised to expand our understanding of its molecular underpinnings and potential treatment options.
4. The effect on quality of life is significant both in patients living with hATTR amyloidosis and their caregivers.
hATTR amyloidosis imposes a multifaceted burden on patients and their caregivers as the disease progresses. Symptoms range from sensorimotor impairment and gastrointestinal or autonomic dysfunction to heart failure, leading to significant health-related quality-of-life deficits. The systemic nature of hATTR amyloidosis significantly affects patients› lifestyles, daily activities, and general well-being, especially because it typically manifests in adulthood — a crucial time for occupational changes. The progression of hATTR amyloidosis exacerbates the challenges in maintaining employment and managing household chores, with symptomatic patients often unable to work and experiencing difficulties with absenteeism and presenteeism when they are able to work.
hATTR amyloidosis leads to physical, mental, occupational, and social limitations for patients, and it also places a considerable strain on their families and caregivers, who report poor mental health, work impairment, and a high time commitment (mean, 45.9 h/wk) to providing care.
5. There have been significant advancements in therapeutic options for early-stage hATTR amyloidosis.
After diagnosis, prompt initiation of treatment is recommended to delay the progression of hATTR amyloidosis; a multidisciplinary approach is essential, incorporating anti-amyloid therapy to inhibit further production and/or deposition of amyloid aggregates. Treatment strategies also include addressing symptomatic therapy and managing cardiac, renal, and ocular involvement. Although many therapies have been developed, especially for the early stages of hATTR amyloidosis, therapeutic benefits for patients with advanced disease remain limited.
Recent advancements in the treatment of hATTR amyloidosis have introduced RNA-targeted therapies including patisiran, vutrisiran, and eplontersen, which have shown efficacy in reducing hepatic TTR synthesis and the aggregation of misfolded monomers into amyloid deposits. These therapies, ranging from small interfering RNA formulations to antisense oligonucleotides, offer benefits in managing both cardiomyopathy and neuropathy associated with hATTR amyloidosis , administered through various methods, including intravenous infusions and subcutaneous injections. In addition, the stabilization of TTR tetramers with the use of drugs such as tafamidis and diflunisal has effectively prevented the formation of amyloidogenic monomers. Moreover, other investigational agents, including TTR stabilizers like acoramidis and tolcapone, as well as novel compounds that inhibit amyloid formation and disrupt fibrils, are expanding the therapeutic landscape for hATTR amyloidosis , providing hope for improved management of this complex condition.
Dr. Gertz is a professor and consultant in the Department of Hematology, Mayo Clinic, Rochester, Minnesota. He has disclosed the following relevant financial relationships: Received income in an amount equal to or greater than $250 from AstraZeneca, Ionis, and Alnylym.
A version of this article appeared on Medscape.com.
Amyloidosis is a condition marked by the accumulation of insoluble beta-sheet fibrillar protein aggregates in tissues that can be acquired or hereditary. Hereditary amyloidogenic transthyretin (hATTR) amyloidosis is an autosomal-dominant disease caused by pathogenic variants in the TTR gene. The TTR protein is essential for transporting thyroxine and retinol-binding protein and is primarily synthesized in the liver, becoming unstable as a result of the pathogenic mutations. Inherited pathogenic variants lead to the protein’s misfolding, aggregation, and deposition as amyloid fibrils in different organs, resulting in progressive multisystem dysfunction. hATTR amyloidosis is a heterogenous disease, characterized by a wide range of clinical manifestations affecting the peripheral (both somatic and autonomic) nervous system, heart, kidneys, and central nervous system (CNS); however, the heart and peripheral nerves appear to be the main targets of the TTR-related pathologic process. Without treatment, the prognosis is poor, with an average life expectancy of 7-11 years; however, in recent years, the development of new therapeutics has brought new hope to patients.
Here are five things to know about hereditary amyloidosis.
1. Diagnosis of hereditary amyloidosis requires a high level of suspicion.
The diagnosis of hATTR amyloidosis presents a significant challenge, particularly in nonendemic regions where a lack of family history and heterogeneity of clinical presentation can delay diagnosis by 4-5 years. A timely diagnosis requires clinicians to maintain a high index of suspicion, especially when evaluating patients with neuropathic symptoms. Early diagnosis is crucial to begin patients on recently available disease-modifying therapies that can slow the disease course. Failure to recognize is the major barrier to improved patient outcomes.
Confirming the diagnosis involves detecting amyloid deposits in tissue biopsy specimens from various possible sites, including the skin, nerves, myocardium, and others. However, the diagnosis can be challenging owing to the uneven distribution of amyloid fibrils, sometimes requiring multiple biopsies or alternative diagnostic approaches, such as TTR gene sequencing, to confirm the presence of an amyloidogenic pathogenic variant. Biopsy for hATTR amyloidosis is not required if imaging of the clinical phenotype and genetic testing are consistent.
Once diagnosed, the assessment of organ involvement is essential, using nerve conduction studies, cardiac investigations (eg, echocardiography, ECG, scintigraphy), ophthalmologic assessments, and complete renal function evaluations to fully understand the extent of disease impact.
2. Hereditary amyloidosis diseases are classified into two primary categories.
Hereditary amyloidosis represents a group of diseases caused by inherited gene mutations and is classified into two main types: ATTR (transthyretin-related) and non-TTR. Most cases of hereditary amyloidosis are associated with the TTR gene. Mutations in this protein lead to different forms of ATTR amyloidosis, categorized on the basis of the specific mutation involved, such as hATTR50M (genotype Val50Met), which is the most prevalent form.
ATTR mutations result in a variety of health issues, manifesting in three primary forms:
- Neuropathic ATTR (genotype Val50Met): Early symptoms include sensorimotor polyneuropathy of the legs, carpal tunnel syndrome, autonomic dysfunction, constipation/diarrhea, and impotence; late symptoms include cardiomyopathy, vitreous opacities, glaucoma, nephropathy, and CNS symptoms.
- Cardiac ATTR (genotype Val142Ile): This type is characterized by cardiomegaly, conduction block, arrhythmia, anginal pain, congestive heart failure, and sudden death.
- Leptomeningeal ATTR (genotype Asp38Gly): This is characterized by transient focal neurologic episodes, intracerebral and/or subarachnoid hemorrhages, dementia, ataxia, and psychosis.
Non-TTR amyloidoses are rarer than are ATTR variations and involve mutations in different genes that also have significant health impacts. These include proteins such as apolipoprotein AI, fibrinogen A alpha, lysozyme, apolipoprotein AII, gelsolin, and cystatin C. Each type contributes to a range of symptoms and requires individualized management approaches.
3. Heightened disease awareness has increased the recognized prevalence of hereditary amyloidosis.
hATTR amyloidosis has historically been recognized as a rare disease, with significant clusters in Portugal, Brazil, Sweden, and Japan and alongside smaller foci in regions such as Cyprus and Majorca. This disease›s variable incidence across Europe is now perceived to be on the rise. It is attributed to heightened disease awareness among healthcare providers and the broader availability of genetic testing, extending its recognized impact to at least 29 countries globally. The genetic landscape of hATTR amyloidosis is diverse, with over 140 mutations identified in the TTR gene. Among these, the Val50Met mutation is particularly notable for its association with large patient clusters in the endemic regions.
Morbidity and mortality associated with hATTR amyloidosis are significant, with an average lifespan of 7-11 years post diagnosis; however, survival rates can vary widely depending on the specific genetic variant and organ involvement. Early diagnosis can substantially improve outcomes; yet, for many, the prognosis remains poor, especially in cases dominated by cardiomyopathy. Genetics play a central role in the disease›s transmission, with autosomal-dominant inheritance patterns and high penetrance among carriers of pathogenic mutations. Research continues to uncover the broad spectrum of genetic variations contributing to hATTR amyloidosis, with ongoing studies poised to expand our understanding of its molecular underpinnings and potential treatment options.
4. The effect on quality of life is significant both in patients living with hATTR amyloidosis and their caregivers.
hATTR amyloidosis imposes a multifaceted burden on patients and their caregivers as the disease progresses. Symptoms range from sensorimotor impairment and gastrointestinal or autonomic dysfunction to heart failure, leading to significant health-related quality-of-life deficits. The systemic nature of hATTR amyloidosis significantly affects patients› lifestyles, daily activities, and general well-being, especially because it typically manifests in adulthood — a crucial time for occupational changes. The progression of hATTR amyloidosis exacerbates the challenges in maintaining employment and managing household chores, with symptomatic patients often unable to work and experiencing difficulties with absenteeism and presenteeism when they are able to work.
hATTR amyloidosis leads to physical, mental, occupational, and social limitations for patients, and it also places a considerable strain on their families and caregivers, who report poor mental health, work impairment, and a high time commitment (mean, 45.9 h/wk) to providing care.
5. There have been significant advancements in therapeutic options for early-stage hATTR amyloidosis.
After diagnosis, prompt initiation of treatment is recommended to delay the progression of hATTR amyloidosis; a multidisciplinary approach is essential, incorporating anti-amyloid therapy to inhibit further production and/or deposition of amyloid aggregates. Treatment strategies also include addressing symptomatic therapy and managing cardiac, renal, and ocular involvement. Although many therapies have been developed, especially for the early stages of hATTR amyloidosis, therapeutic benefits for patients with advanced disease remain limited.
Recent advancements in the treatment of hATTR amyloidosis have introduced RNA-targeted therapies including patisiran, vutrisiran, and eplontersen, which have shown efficacy in reducing hepatic TTR synthesis and the aggregation of misfolded monomers into amyloid deposits. These therapies, ranging from small interfering RNA formulations to antisense oligonucleotides, offer benefits in managing both cardiomyopathy and neuropathy associated with hATTR amyloidosis , administered through various methods, including intravenous infusions and subcutaneous injections. In addition, the stabilization of TTR tetramers with the use of drugs such as tafamidis and diflunisal has effectively prevented the formation of amyloidogenic monomers. Moreover, other investigational agents, including TTR stabilizers like acoramidis and tolcapone, as well as novel compounds that inhibit amyloid formation and disrupt fibrils, are expanding the therapeutic landscape for hATTR amyloidosis , providing hope for improved management of this complex condition.
Dr. Gertz is a professor and consultant in the Department of Hematology, Mayo Clinic, Rochester, Minnesota. He has disclosed the following relevant financial relationships: Received income in an amount equal to or greater than $250 from AstraZeneca, Ionis, and Alnylym.
A version of this article appeared on Medscape.com.
Major Gaps in Care and Management of Neurologic Diseases
DENVER –
Investigators led by Nikki Win, PhD, medical manager/team lead, OMNI Scientific Strategy and Collaborations, US Medical Affairs, Genentech/Roche, found that patients with Parkinson’s disease were referred to a specialist most often, followed by those with MS and those with AD.
The findings were presented at the 2024 annual meeting of the American Academy of Neurology (AAN).
National Neurologist Shortage
The national neurologist shortage, coupled with the growing incidence of Alzheimer’s disease, Parkinson’s disease, MS, and other conditions has led the AAN and other organizations to call for expanding the role of primary care physicians in the diagnosis and management of neurologic disorders, the leading global cause of disability.
“These neurological conditions are increasing in prevalence and there’s a limited number of neurologists, so we wanted to understand what this looks like in the US,” Dr. Win said.
“There is a need to understand the patient journey from primary care to neurology care, from presentation of a suspected neurological disorder to diagnosis, referral to a specialist, and the time elapsed before the specialist visit for Alzheimer’s disease, MS, and Parkinson’s disease in the US,” Dr. Win added.
Timely and accurate diagnoses of neurologic disorders can optimize treatment outcomes. Because many of these diseases are first detected during a visit with a primary care physician, it is important to understand the timeline from the initial visit to a specialist referral, the investigators noted.
Analyzing Trends in Specialist Referrals
Using claims data from the Optum Normative Health Information database, researchers identified 48,525 adults with Alzheimer’s disease, 26,431 with Parkinson’s disease, and 8169 with MS who received a diagnosis from a primary care physician between 2016 and 2021.
They examined the proportion, timing, and demographic factors associated with referrals from primary care clinicians or other healthcare providers to specialists including neurologists, neurosurgeons, psychiatrists, and geriatric medicine specialists.
Results showed that patients with Parkinson’s disease were referred to a specialist most often (53%), followed by those with MS (42%) and those with Alzheimer’s disease (27%).
Individuals with Alzheimer’s disease waited the longest for a specialist referral, with a median of 10 months between the time of referral and the first specialist visit compared with 5.7 months for patients with Parkinson’s disease and 2.6 months for MS patients.
“Some patients with common conditions like Alzheimer’s disease, MS, and Parkinson’s disease don’t see a neurologist, and when they do, it can take as long as 10 months,” said Dr. Win.
Using zip code heatmaps, researchers found that the proportion of referrals for all neurologic disorders was higher in the Midwest and Northeast, whereas patients in the South and West were less likely to receive a referral.
Referrals for Alzheimer’s disease were low nationwide, except for some areas of Michigan and New England. California had the lowest referral rate for MS, followed by regions in the South and Northeast. Patients with Parkinson’s disease living in the Midwest and Northeast were more likely than those in the West to receive a specialist referral.
Previous studies have reported regional shortages of neurologists, said Dr. Win. “Our data seem to correlate that in terms of the areas with lower referral patterns, but as to whether that is causative or correlative, we don’t know.”
Odds of referral were also influenced by demographic characteristics such as sex, age, race, and ethnicity, investigators found.
For example, there were fewer referrals with increasing age across all three neurologic disorders, and men were more likely than women to be referred for Alzheimer’s disease and Parkinson’s disease. Compared with White patients, Parkinson’s disease referrals were less likely among African American, Asian, and Hispanic patients and Alzheimer’s disease referrals were less common among Asian and Hispanic patients.
Insurance status also affected referrals. People with MS and Parkinson’s disease who had commercial insurance were referred more often than were those with Medicare Advantage, said Dr. Win.
She also noted, “Additional research is needed to understand how being referred or not being referred to a neurologist actually impacts patient treatment, care and outcomes.”
Neurology Challenges
Commenting on the research, Thomas Vidic, MD, a community neurologist in Elkhart, Indiana, and clinical professor of neurology at Indiana University School of Medicine at South Bend, said that he was surprised by the variation in wait times for patients.
This, he said, could reflect a study limitation or a higher comfort level among primary care doctors in treating dementia.
With respect to MS, Dr. Vidic said that he believes primary care physicians may not be uncertain about prescribing the approved medications for the disease because there are so many of them.
In addition, patients with Alzheimer’s disease are older and perhaps less accepting of being referred to a specialist that may be hours away.
The bottom line for Dr. Vidic, though, is the lack of specialists. “It comes back to the fact we’re not doing a good job of having community neurologists available to take care of these problems,” he said.
The issue of community neurologist shortages was underlined by the study’s findings about geographic gaps in specialist referrals across the country, he said.
Neurologists make up about 2% of the medical workforce and this has remained static for some time, Dr. Vidic noted. Meanwhile, people are living longer and developing more neurologic diseases.
Dr. Vidic also pointed to the lack of neurology training programs. “There has not been a significant change in the number of programs in the last 10-15 years,” he said.
Study funding was not disclosed. Dr. Win reports receiving personal compensation for serving as an employee of Genentech and has stock in Genentech. Dr. Vidic reports no relevant financial disclosures.
A version of this article appeared on Medscape.com.
DENVER –
Investigators led by Nikki Win, PhD, medical manager/team lead, OMNI Scientific Strategy and Collaborations, US Medical Affairs, Genentech/Roche, found that patients with Parkinson’s disease were referred to a specialist most often, followed by those with MS and those with AD.
The findings were presented at the 2024 annual meeting of the American Academy of Neurology (AAN).
National Neurologist Shortage
The national neurologist shortage, coupled with the growing incidence of Alzheimer’s disease, Parkinson’s disease, MS, and other conditions has led the AAN and other organizations to call for expanding the role of primary care physicians in the diagnosis and management of neurologic disorders, the leading global cause of disability.
“These neurological conditions are increasing in prevalence and there’s a limited number of neurologists, so we wanted to understand what this looks like in the US,” Dr. Win said.
“There is a need to understand the patient journey from primary care to neurology care, from presentation of a suspected neurological disorder to diagnosis, referral to a specialist, and the time elapsed before the specialist visit for Alzheimer’s disease, MS, and Parkinson’s disease in the US,” Dr. Win added.
Timely and accurate diagnoses of neurologic disorders can optimize treatment outcomes. Because many of these diseases are first detected during a visit with a primary care physician, it is important to understand the timeline from the initial visit to a specialist referral, the investigators noted.
Analyzing Trends in Specialist Referrals
Using claims data from the Optum Normative Health Information database, researchers identified 48,525 adults with Alzheimer’s disease, 26,431 with Parkinson’s disease, and 8169 with MS who received a diagnosis from a primary care physician between 2016 and 2021.
They examined the proportion, timing, and demographic factors associated with referrals from primary care clinicians or other healthcare providers to specialists including neurologists, neurosurgeons, psychiatrists, and geriatric medicine specialists.
Results showed that patients with Parkinson’s disease were referred to a specialist most often (53%), followed by those with MS (42%) and those with Alzheimer’s disease (27%).
Individuals with Alzheimer’s disease waited the longest for a specialist referral, with a median of 10 months between the time of referral and the first specialist visit compared with 5.7 months for patients with Parkinson’s disease and 2.6 months for MS patients.
“Some patients with common conditions like Alzheimer’s disease, MS, and Parkinson’s disease don’t see a neurologist, and when they do, it can take as long as 10 months,” said Dr. Win.
Using zip code heatmaps, researchers found that the proportion of referrals for all neurologic disorders was higher in the Midwest and Northeast, whereas patients in the South and West were less likely to receive a referral.
Referrals for Alzheimer’s disease were low nationwide, except for some areas of Michigan and New England. California had the lowest referral rate for MS, followed by regions in the South and Northeast. Patients with Parkinson’s disease living in the Midwest and Northeast were more likely than those in the West to receive a specialist referral.
Previous studies have reported regional shortages of neurologists, said Dr. Win. “Our data seem to correlate that in terms of the areas with lower referral patterns, but as to whether that is causative or correlative, we don’t know.”
Odds of referral were also influenced by demographic characteristics such as sex, age, race, and ethnicity, investigators found.
For example, there were fewer referrals with increasing age across all three neurologic disorders, and men were more likely than women to be referred for Alzheimer’s disease and Parkinson’s disease. Compared with White patients, Parkinson’s disease referrals were less likely among African American, Asian, and Hispanic patients and Alzheimer’s disease referrals were less common among Asian and Hispanic patients.
Insurance status also affected referrals. People with MS and Parkinson’s disease who had commercial insurance were referred more often than were those with Medicare Advantage, said Dr. Win.
She also noted, “Additional research is needed to understand how being referred or not being referred to a neurologist actually impacts patient treatment, care and outcomes.”
Neurology Challenges
Commenting on the research, Thomas Vidic, MD, a community neurologist in Elkhart, Indiana, and clinical professor of neurology at Indiana University School of Medicine at South Bend, said that he was surprised by the variation in wait times for patients.
This, he said, could reflect a study limitation or a higher comfort level among primary care doctors in treating dementia.
With respect to MS, Dr. Vidic said that he believes primary care physicians may not be uncertain about prescribing the approved medications for the disease because there are so many of them.
In addition, patients with Alzheimer’s disease are older and perhaps less accepting of being referred to a specialist that may be hours away.
The bottom line for Dr. Vidic, though, is the lack of specialists. “It comes back to the fact we’re not doing a good job of having community neurologists available to take care of these problems,” he said.
The issue of community neurologist shortages was underlined by the study’s findings about geographic gaps in specialist referrals across the country, he said.
Neurologists make up about 2% of the medical workforce and this has remained static for some time, Dr. Vidic noted. Meanwhile, people are living longer and developing more neurologic diseases.
Dr. Vidic also pointed to the lack of neurology training programs. “There has not been a significant change in the number of programs in the last 10-15 years,” he said.
Study funding was not disclosed. Dr. Win reports receiving personal compensation for serving as an employee of Genentech and has stock in Genentech. Dr. Vidic reports no relevant financial disclosures.
A version of this article appeared on Medscape.com.
DENVER –
Investigators led by Nikki Win, PhD, medical manager/team lead, OMNI Scientific Strategy and Collaborations, US Medical Affairs, Genentech/Roche, found that patients with Parkinson’s disease were referred to a specialist most often, followed by those with MS and those with AD.
The findings were presented at the 2024 annual meeting of the American Academy of Neurology (AAN).
National Neurologist Shortage
The national neurologist shortage, coupled with the growing incidence of Alzheimer’s disease, Parkinson’s disease, MS, and other conditions has led the AAN and other organizations to call for expanding the role of primary care physicians in the diagnosis and management of neurologic disorders, the leading global cause of disability.
“These neurological conditions are increasing in prevalence and there’s a limited number of neurologists, so we wanted to understand what this looks like in the US,” Dr. Win said.
“There is a need to understand the patient journey from primary care to neurology care, from presentation of a suspected neurological disorder to diagnosis, referral to a specialist, and the time elapsed before the specialist visit for Alzheimer’s disease, MS, and Parkinson’s disease in the US,” Dr. Win added.
Timely and accurate diagnoses of neurologic disorders can optimize treatment outcomes. Because many of these diseases are first detected during a visit with a primary care physician, it is important to understand the timeline from the initial visit to a specialist referral, the investigators noted.
Analyzing Trends in Specialist Referrals
Using claims data from the Optum Normative Health Information database, researchers identified 48,525 adults with Alzheimer’s disease, 26,431 with Parkinson’s disease, and 8169 with MS who received a diagnosis from a primary care physician between 2016 and 2021.
They examined the proportion, timing, and demographic factors associated with referrals from primary care clinicians or other healthcare providers to specialists including neurologists, neurosurgeons, psychiatrists, and geriatric medicine specialists.
Results showed that patients with Parkinson’s disease were referred to a specialist most often (53%), followed by those with MS (42%) and those with Alzheimer’s disease (27%).
Individuals with Alzheimer’s disease waited the longest for a specialist referral, with a median of 10 months between the time of referral and the first specialist visit compared with 5.7 months for patients with Parkinson’s disease and 2.6 months for MS patients.
“Some patients with common conditions like Alzheimer’s disease, MS, and Parkinson’s disease don’t see a neurologist, and when they do, it can take as long as 10 months,” said Dr. Win.
Using zip code heatmaps, researchers found that the proportion of referrals for all neurologic disorders was higher in the Midwest and Northeast, whereas patients in the South and West were less likely to receive a referral.
Referrals for Alzheimer’s disease were low nationwide, except for some areas of Michigan and New England. California had the lowest referral rate for MS, followed by regions in the South and Northeast. Patients with Parkinson’s disease living in the Midwest and Northeast were more likely than those in the West to receive a specialist referral.
Previous studies have reported regional shortages of neurologists, said Dr. Win. “Our data seem to correlate that in terms of the areas with lower referral patterns, but as to whether that is causative or correlative, we don’t know.”
Odds of referral were also influenced by demographic characteristics such as sex, age, race, and ethnicity, investigators found.
For example, there were fewer referrals with increasing age across all three neurologic disorders, and men were more likely than women to be referred for Alzheimer’s disease and Parkinson’s disease. Compared with White patients, Parkinson’s disease referrals were less likely among African American, Asian, and Hispanic patients and Alzheimer’s disease referrals were less common among Asian and Hispanic patients.
Insurance status also affected referrals. People with MS and Parkinson’s disease who had commercial insurance were referred more often than were those with Medicare Advantage, said Dr. Win.
She also noted, “Additional research is needed to understand how being referred or not being referred to a neurologist actually impacts patient treatment, care and outcomes.”
Neurology Challenges
Commenting on the research, Thomas Vidic, MD, a community neurologist in Elkhart, Indiana, and clinical professor of neurology at Indiana University School of Medicine at South Bend, said that he was surprised by the variation in wait times for patients.
This, he said, could reflect a study limitation or a higher comfort level among primary care doctors in treating dementia.
With respect to MS, Dr. Vidic said that he believes primary care physicians may not be uncertain about prescribing the approved medications for the disease because there are so many of them.
In addition, patients with Alzheimer’s disease are older and perhaps less accepting of being referred to a specialist that may be hours away.
The bottom line for Dr. Vidic, though, is the lack of specialists. “It comes back to the fact we’re not doing a good job of having community neurologists available to take care of these problems,” he said.
The issue of community neurologist shortages was underlined by the study’s findings about geographic gaps in specialist referrals across the country, he said.
Neurologists make up about 2% of the medical workforce and this has remained static for some time, Dr. Vidic noted. Meanwhile, people are living longer and developing more neurologic diseases.
Dr. Vidic also pointed to the lack of neurology training programs. “There has not been a significant change in the number of programs in the last 10-15 years,” he said.
Study funding was not disclosed. Dr. Win reports receiving personal compensation for serving as an employee of Genentech and has stock in Genentech. Dr. Vidic reports no relevant financial disclosures.
A version of this article appeared on Medscape.com.
FROM AAN 2024
Three Conditions for Which Cannabis Appears to Help
The utility of cannabinoids to treat most medical conditions remains uncertain at best, but for at least three indications the data lean in favor of effectiveness, Ellie Grossman, MD, MPH, told attendees recently at the 2024 American College of Physicians Internal Medicine meeting.
Those are neuropathic pain, chemotherapy-induced nausea or vomiting, and spasticity in people with multiple sclerosis, said Dr. Grossman, an instructor at Harvard Medical School in Boston and medical director for primary care/behavioral health integration at Cambridge Health Alliance in Somerville, Massachusetts.
Dearth of Research Persists
Research is sorely lacking and of low quality in the field for many reasons, Dr. Grossman said. Most of the products tested come from outside the United States and often are synthetic and taken orally — which does not match the real-world use when patients go to dispensaries for cannabis derived directly from plants (or the plant product itself). And studies often rely on self-report.
Chronic pain is by far the top reason patients say they use medical cannabis, Dr. Grossman said. A Cochrane review of 16 studies found only that the potential benefits of cannabis may outweigh the potential harms for chronic neuropathic pain.
No Evidence in OUD
Dr. Grossman said she is frequently asked if cannabis can help people quit taking opioids. The answer seems to be no. A study published earlier this year in states with legalized medical or recreational cannabis found no difference between rates of opioid overdose compared with states with no such laws. “It seems like it doesn’t do anything to help us with our opioid problem,” she said.
Nor does high-quality evidence exist showing use of cannabis can improve sleep, she said. A 2022 systematic review found fewer than half of studies showed the substance useful for sleep outcomes. “Where studies were positives, it was in people who had chronic pain,” Dr. Grossman noted. Research indicates cannabis may have substantial benefit for chronic pain compared with placebo.
Potential Harms
If the medical benefits of cannabis are murky, the evidence for its potential harms, at least in the short term, are clearer, according to Dr. Grossman. A simplified guideline for prescribing medical cannabinoids in primary care includes sedation, feeling high, dizziness, speech disorders, muscle twitching, hypotension, and several other conditions among the potential hazards of the drug.
But the potential for long-term harm is uncertain. “All the evidence comes from people who have been using it for recreational reasons,” where there may be co-use of tobacco, self-reported outcomes, and recall bias, she said. The characteristics of people using cannabis recreationally often differ from those using it medicinally.
Use With Other Controlled Substances
Dr. Grossman said clinicians should consider whether the co-use of cannabis and other controlled substances, such as benzodiazepines, opioids, or Adderall, raises the potential risks associated with those drugs. “Ultimately it comes down to talking to your patients,” she said. If a toxicity screen shows the presence of controlled substances, ask about their experience with the drugs they are using and let them know your main concern is their safety.
Dr. Grossman reported no relevant financial conflicts of interest.
A version of this article appeared on Medscape.com.
The utility of cannabinoids to treat most medical conditions remains uncertain at best, but for at least three indications the data lean in favor of effectiveness, Ellie Grossman, MD, MPH, told attendees recently at the 2024 American College of Physicians Internal Medicine meeting.
Those are neuropathic pain, chemotherapy-induced nausea or vomiting, and spasticity in people with multiple sclerosis, said Dr. Grossman, an instructor at Harvard Medical School in Boston and medical director for primary care/behavioral health integration at Cambridge Health Alliance in Somerville, Massachusetts.
Dearth of Research Persists
Research is sorely lacking and of low quality in the field for many reasons, Dr. Grossman said. Most of the products tested come from outside the United States and often are synthetic and taken orally — which does not match the real-world use when patients go to dispensaries for cannabis derived directly from plants (or the plant product itself). And studies often rely on self-report.
Chronic pain is by far the top reason patients say they use medical cannabis, Dr. Grossman said. A Cochrane review of 16 studies found only that the potential benefits of cannabis may outweigh the potential harms for chronic neuropathic pain.
No Evidence in OUD
Dr. Grossman said she is frequently asked if cannabis can help people quit taking opioids. The answer seems to be no. A study published earlier this year in states with legalized medical or recreational cannabis found no difference between rates of opioid overdose compared with states with no such laws. “It seems like it doesn’t do anything to help us with our opioid problem,” she said.
Nor does high-quality evidence exist showing use of cannabis can improve sleep, she said. A 2022 systematic review found fewer than half of studies showed the substance useful for sleep outcomes. “Where studies were positives, it was in people who had chronic pain,” Dr. Grossman noted. Research indicates cannabis may have substantial benefit for chronic pain compared with placebo.
Potential Harms
If the medical benefits of cannabis are murky, the evidence for its potential harms, at least in the short term, are clearer, according to Dr. Grossman. A simplified guideline for prescribing medical cannabinoids in primary care includes sedation, feeling high, dizziness, speech disorders, muscle twitching, hypotension, and several other conditions among the potential hazards of the drug.
But the potential for long-term harm is uncertain. “All the evidence comes from people who have been using it for recreational reasons,” where there may be co-use of tobacco, self-reported outcomes, and recall bias, she said. The characteristics of people using cannabis recreationally often differ from those using it medicinally.
Use With Other Controlled Substances
Dr. Grossman said clinicians should consider whether the co-use of cannabis and other controlled substances, such as benzodiazepines, opioids, or Adderall, raises the potential risks associated with those drugs. “Ultimately it comes down to talking to your patients,” she said. If a toxicity screen shows the presence of controlled substances, ask about their experience with the drugs they are using and let them know your main concern is their safety.
Dr. Grossman reported no relevant financial conflicts of interest.
A version of this article appeared on Medscape.com.
The utility of cannabinoids to treat most medical conditions remains uncertain at best, but for at least three indications the data lean in favor of effectiveness, Ellie Grossman, MD, MPH, told attendees recently at the 2024 American College of Physicians Internal Medicine meeting.
Those are neuropathic pain, chemotherapy-induced nausea or vomiting, and spasticity in people with multiple sclerosis, said Dr. Grossman, an instructor at Harvard Medical School in Boston and medical director for primary care/behavioral health integration at Cambridge Health Alliance in Somerville, Massachusetts.
Dearth of Research Persists
Research is sorely lacking and of low quality in the field for many reasons, Dr. Grossman said. Most of the products tested come from outside the United States and often are synthetic and taken orally — which does not match the real-world use when patients go to dispensaries for cannabis derived directly from plants (or the plant product itself). And studies often rely on self-report.
Chronic pain is by far the top reason patients say they use medical cannabis, Dr. Grossman said. A Cochrane review of 16 studies found only that the potential benefits of cannabis may outweigh the potential harms for chronic neuropathic pain.
No Evidence in OUD
Dr. Grossman said she is frequently asked if cannabis can help people quit taking opioids. The answer seems to be no. A study published earlier this year in states with legalized medical or recreational cannabis found no difference between rates of opioid overdose compared with states with no such laws. “It seems like it doesn’t do anything to help us with our opioid problem,” she said.
Nor does high-quality evidence exist showing use of cannabis can improve sleep, she said. A 2022 systematic review found fewer than half of studies showed the substance useful for sleep outcomes. “Where studies were positives, it was in people who had chronic pain,” Dr. Grossman noted. Research indicates cannabis may have substantial benefit for chronic pain compared with placebo.
Potential Harms
If the medical benefits of cannabis are murky, the evidence for its potential harms, at least in the short term, are clearer, according to Dr. Grossman. A simplified guideline for prescribing medical cannabinoids in primary care includes sedation, feeling high, dizziness, speech disorders, muscle twitching, hypotension, and several other conditions among the potential hazards of the drug.
But the potential for long-term harm is uncertain. “All the evidence comes from people who have been using it for recreational reasons,” where there may be co-use of tobacco, self-reported outcomes, and recall bias, she said. The characteristics of people using cannabis recreationally often differ from those using it medicinally.
Use With Other Controlled Substances
Dr. Grossman said clinicians should consider whether the co-use of cannabis and other controlled substances, such as benzodiazepines, opioids, or Adderall, raises the potential risks associated with those drugs. “Ultimately it comes down to talking to your patients,” she said. If a toxicity screen shows the presence of controlled substances, ask about their experience with the drugs they are using and let them know your main concern is their safety.
Dr. Grossman reported no relevant financial conflicts of interest.
A version of this article appeared on Medscape.com.
Antidepressants and Dementia Risk: Reassuring Data
TOPLINE:
, new research suggests.
METHODOLOGY:
- Investigators studied 5511 individuals (58% women; mean age, 71 years) from the Rotterdam study, an ongoing prospective population-based cohort study.
- Participants were free from dementia at baseline, and incident dementia was monitored from baseline until 2018 with repeated cognitive assessments using the Mini-Mental Status Examination (MMSE) and the Geriatric Mental Schedule, as well as MRIs.
- Information on participants’ antidepressant use was extracted from pharmacy records from 1992 until baseline (2002-2008).
- During a mean follow-up of 10 years, 12% of participants developed dementia.
TAKEAWAY:
- Overall, 17% of participants had used antidepressants during the roughly 10-year period prior to baseline, and 4.1% were still using antidepressants at baseline.
- Medication use at baseline was more common in women than in men (21% vs 18%), and use increased with age: From 2.1% in participants aged between 45 and 50 years to 4.5% in those older than 80 years.
- After adjustment for confounders, there was no association between antidepressant use and dementia risk (hazard ratio [HR], 1.14; 95% CI, 0.92-1.41), accelerated cognitive decline, or atrophy of white and gray matter.
- However, tricyclic antidepressant use was associated with increased dementia risk (HR, 1.36; 95% CI, 1.01-1.83) compared with the use of selective serotonin reuptake inhibitors (HR, 1.12; 95% CI, 0.81-1.54).
IN PRACTICE:
“Although prescription of antidepressant medication in older individuals, in particular those with some cognitive impairment, may have acute symptomatic anticholinergic effects that warrant consideration in clinical practice, our results show that long-term antidepressant use does not have lasting effects on cognition or brain health in older adults without indication of cognitive impairment,” the authors wrote.
SOURCE:
Frank J. Wolters, MD, of the Department of Epidemiology and the Department of Radiology and Nuclear Medicine and Alzheimer Center, Erasmus University Medical Center, Rotterdam, the Netherlands, was the senior author on this study that was published online in Alzheimer’s and Dementia.
LIMITATIONS:
Limitations included the concern that although exclusion of participants with MMSE < 26 at baseline prevented reversed causation (ie, antidepressant use in response to depression during the prodromal phase of dementia), it may have introduced selection bias by disregarding the effects of antidepressant use prior to baseline and excluding participants with lower education.
DISCLOSURES:
This study was conducted as part of the Netherlands Consortium of Dementia Cohorts, which receives funding in the context of Deltaplan Dementie from ZonMW Memorabel and Alzheimer Nederland. Further funding was also obtained from the Stichting Erasmus Trustfonds. This study was further supported by a 2020 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation. The authors reported no conflicts of interest or relevant financial relationships.
A version of this article appeared on Medscape.com.
TOPLINE:
, new research suggests.
METHODOLOGY:
- Investigators studied 5511 individuals (58% women; mean age, 71 years) from the Rotterdam study, an ongoing prospective population-based cohort study.
- Participants were free from dementia at baseline, and incident dementia was monitored from baseline until 2018 with repeated cognitive assessments using the Mini-Mental Status Examination (MMSE) and the Geriatric Mental Schedule, as well as MRIs.
- Information on participants’ antidepressant use was extracted from pharmacy records from 1992 until baseline (2002-2008).
- During a mean follow-up of 10 years, 12% of participants developed dementia.
TAKEAWAY:
- Overall, 17% of participants had used antidepressants during the roughly 10-year period prior to baseline, and 4.1% were still using antidepressants at baseline.
- Medication use at baseline was more common in women than in men (21% vs 18%), and use increased with age: From 2.1% in participants aged between 45 and 50 years to 4.5% in those older than 80 years.
- After adjustment for confounders, there was no association between antidepressant use and dementia risk (hazard ratio [HR], 1.14; 95% CI, 0.92-1.41), accelerated cognitive decline, or atrophy of white and gray matter.
- However, tricyclic antidepressant use was associated with increased dementia risk (HR, 1.36; 95% CI, 1.01-1.83) compared with the use of selective serotonin reuptake inhibitors (HR, 1.12; 95% CI, 0.81-1.54).
IN PRACTICE:
“Although prescription of antidepressant medication in older individuals, in particular those with some cognitive impairment, may have acute symptomatic anticholinergic effects that warrant consideration in clinical practice, our results show that long-term antidepressant use does not have lasting effects on cognition or brain health in older adults without indication of cognitive impairment,” the authors wrote.
SOURCE:
Frank J. Wolters, MD, of the Department of Epidemiology and the Department of Radiology and Nuclear Medicine and Alzheimer Center, Erasmus University Medical Center, Rotterdam, the Netherlands, was the senior author on this study that was published online in Alzheimer’s and Dementia.
LIMITATIONS:
Limitations included the concern that although exclusion of participants with MMSE < 26 at baseline prevented reversed causation (ie, antidepressant use in response to depression during the prodromal phase of dementia), it may have introduced selection bias by disregarding the effects of antidepressant use prior to baseline and excluding participants with lower education.
DISCLOSURES:
This study was conducted as part of the Netherlands Consortium of Dementia Cohorts, which receives funding in the context of Deltaplan Dementie from ZonMW Memorabel and Alzheimer Nederland. Further funding was also obtained from the Stichting Erasmus Trustfonds. This study was further supported by a 2020 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation. The authors reported no conflicts of interest or relevant financial relationships.
A version of this article appeared on Medscape.com.
TOPLINE:
, new research suggests.
METHODOLOGY:
- Investigators studied 5511 individuals (58% women; mean age, 71 years) from the Rotterdam study, an ongoing prospective population-based cohort study.
- Participants were free from dementia at baseline, and incident dementia was monitored from baseline until 2018 with repeated cognitive assessments using the Mini-Mental Status Examination (MMSE) and the Geriatric Mental Schedule, as well as MRIs.
- Information on participants’ antidepressant use was extracted from pharmacy records from 1992 until baseline (2002-2008).
- During a mean follow-up of 10 years, 12% of participants developed dementia.
TAKEAWAY:
- Overall, 17% of participants had used antidepressants during the roughly 10-year period prior to baseline, and 4.1% were still using antidepressants at baseline.
- Medication use at baseline was more common in women than in men (21% vs 18%), and use increased with age: From 2.1% in participants aged between 45 and 50 years to 4.5% in those older than 80 years.
- After adjustment for confounders, there was no association between antidepressant use and dementia risk (hazard ratio [HR], 1.14; 95% CI, 0.92-1.41), accelerated cognitive decline, or atrophy of white and gray matter.
- However, tricyclic antidepressant use was associated with increased dementia risk (HR, 1.36; 95% CI, 1.01-1.83) compared with the use of selective serotonin reuptake inhibitors (HR, 1.12; 95% CI, 0.81-1.54).
IN PRACTICE:
“Although prescription of antidepressant medication in older individuals, in particular those with some cognitive impairment, may have acute symptomatic anticholinergic effects that warrant consideration in clinical practice, our results show that long-term antidepressant use does not have lasting effects on cognition or brain health in older adults without indication of cognitive impairment,” the authors wrote.
SOURCE:
Frank J. Wolters, MD, of the Department of Epidemiology and the Department of Radiology and Nuclear Medicine and Alzheimer Center, Erasmus University Medical Center, Rotterdam, the Netherlands, was the senior author on this study that was published online in Alzheimer’s and Dementia.
LIMITATIONS:
Limitations included the concern that although exclusion of participants with MMSE < 26 at baseline prevented reversed causation (ie, antidepressant use in response to depression during the prodromal phase of dementia), it may have introduced selection bias by disregarding the effects of antidepressant use prior to baseline and excluding participants with lower education.
DISCLOSURES:
This study was conducted as part of the Netherlands Consortium of Dementia Cohorts, which receives funding in the context of Deltaplan Dementie from ZonMW Memorabel and Alzheimer Nederland. Further funding was also obtained from the Stichting Erasmus Trustfonds. This study was further supported by a 2020 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation. The authors reported no conflicts of interest or relevant financial relationships.
A version of this article appeared on Medscape.com.
Mandatory DMV Reporting Tied to Dementia Underdiagnosis
, new research suggests.
Investigators found that primary care physicians (PCPs) in states with clinician reporting mandates had a 59% higher probability of underdiagnosing dementia compared with their counterparts in states that require patients to self-report or that have no reporting mandates.
“Our findings in this cross-sectional study raise concerns about potential adverse effects of mandatory clinician reporting for dementia diagnosis and underscore the need for careful consideration of the effect of such policies,” wrote the investigators, led by Soeren Mattke, MD, DSc, director of the USC Brain Health Observatory and research professor of economics at the University of Southern California, Los Angeles.
The study was published online in JAMA Network Open.
Lack of Guidance
As the US population ages, the number of older drivers is increasing, with 55.8 million drivers 65 years old or older. Approximately 7 million people in this age group have dementia — an estimate that is expected to increase to nearly 12 million by 2040.
The aging population raises a “critical policy question” about how to ensure road safety. Although the American Medical Association’s Code of Ethics outlines a physician’s obligation to identify drivers with medical impairments that impede safe driving, guidance restricting cognitively impaired drivers from driving is lacking.
In addition, evidence as to whether cognitive impairment indeed poses a threat to driving safety is mixed and has led to a lack of uniform policies with respect to reporting dementia.
Four states explicitly require clinicians to report dementia diagnoses to the DMV, which will then determine the patient’s fitness to drive, whereas 14 states require people with dementia to self-report. The remaining states have no explicit reporting requirements.
The issue of mandatory reporting is controversial, the researchers noted. On the one hand, physicians could protect patients and others by reporting potentially unsafe drivers.
On the other hand, evidence of an association with lower accident risks in patients with dementia is sparse and mandatory reporting may adversely affect physician-patient relationships. Empirical evidence for unintended consequences of reporting laws is lacking.
To examine the potential link between dementia underdiagnosis and mandatory reporting policies, the investigators analyzed the 100% data from the Medicare fee-for-service program and Medicare Advantage plans from 2017 to 2019, which included 223,036 PCPs with a panel of 25 or more Medicare patients.
The researchers examined dementia diagnosis rates in the patient panel of PCPs, rather than neurologists or gerontologists, regardless of who documented the diagnosis. Dr. Mattke said that it is possible that the diagnosis was established after referral to a specialist.
Each physician’s expected number of dementia cases was estimated using a predictive model based on patient characteristics. The researchers then compared the estimate with observed dementia diagnoses, thereby identifying clinicians who underdiagnosed dementia after sampling errors were accounted for.
‘Heavy-Handed Interference’
The researchers adjusted for several covariates potentially associated with a clinician’s probability of underdiagnosing dementia. These included sex, office location, practice specialty, racial/ethnic composition of the patient panel, and percentage of patients dually eligible for Medicare and Medicaid. The table shows PCP characteristics.
Adjusted results showed that PCPs practicing in states with clinician reporting mandates had a 12.4% (95% confidence interval [CI], 10.5%-14.2%) probability of underdiagnosing dementia versus 7.8% (95% CI, 6.9%-8.7%) in states with self-reporting and 7.7% (95% CI, 6.9%-8.4%) in states with no mandates, translating into a 4–percentage point difference (P < .001).
“Our study is the first to provide empirical evidence for the potential adverse effects of reporting policies,” the researchers noted. “Although we found that some clinicians underdiagnosed dementia regardless of state mandates, the key finding of this study reveals that primary care clinicians who practice in states with clinician reporting mandates were 59% more likely to do so…compared with those states with no reporting requirements…or driver self-reporting requirements.”
The investigators suggested that one potential explanation for underdiagnosis is patient resistance to cognitive testing. If patients were aware that the clinician was obligated by law to report their dementia diagnosis to the DMV, “they might be more inclined to conceal their symptoms or refuse further assessments, in addition to the general stigma and resistance to a formal assessment after a positive dementia screening result.”
“The findings suggest that policymakers might want to rethink those physician reporting mandates, since we also could not find conclusive evidence that they improve road safety,” Dr. Mattke said. “Maybe patients and their physicians can arrive at a sensible approach to determine driving fitness without such heavy-handed interference.”
However, he cautioned that the findings are not definitive and further study is needed before firm recommendations either for or against mandatory reporting.
In addition, the researchers noted several study limitations. One is that dementia underdiagnosis may also be associated with factors not captured in their model, including physician-patient relationships, health literacy, or language barriers.
However, Dr. Mattke noted, “ my sense is that those unobservable factors are not systematically related to state reporting policies and having omitted them would therefore not bias our results.”
Experts Weigh In
Commenting on the research, Morgan Daven, MA, the Alzheimer’s Association vice president of health systems, said that dementia is widely and significantly underdiagnosed, and not only in the states with dementia reporting mandates. Many factors may contribute to underdiagnosis, and although the study shows an association between reporting mandates and underdiagnosis, it does not demonstrate causation.
That said, Mr. Daven added, “fear and stigma related to dementia may inhibit the clinician, the patient, and their family from pursuing detection and diagnosis for dementia. As a society, we need to address dementia fear and stigma for all parties.”
He noted that useful tools include healthcare policies, workforce training, public awareness and education, and public policies to mitigate fear and stigma and their negative effects on diagnosis, care, support, and communication.
A potential study limitation is that it relied only on diagnoses by PCPs. Mr. Daven noted that the diagnosis of Alzheimer’ disease — the most common cause of dementia — is confirmation of amyloid buildup via a biomarker test, using PET or cerebrospinal fluid analysis.
“Both of these tests are extremely limited in their use and accessibility in a primary care setting. Inclusion of diagnoses by dementia specialists would provide a more complete picture,” he said.
Mr. Daven added that the Alzheimer’s Association encourages families to proactively discuss driving and other disease-related safety concerns as soon as possible. The Alzheimer’s Association Dementia and Driving webpage offers tips and strategies to discuss driving concerns with a family member.
In an accompanying editorial, Donald Redelmeier, MD, MS(HSR), and Vidhi Bhatt, BSc, both of the Department of Medicine, University of Toronto, differentiate the mandate for physicians to warn patients with dementia about traffic safety from the mandate for reporting child maltreatment, gunshot victims, or communicable diseases. They noted that mandated warnings “are not easy, can engender patient dissatisfaction, and need to be handled with tact.”
Yet, they pointed out, “breaking bad news is what practicing medicine entails.” They emphasized that, regardless of government mandates, “counseling patients for more road safety is an essential skill for clinicians in diverse states who hope to help their patients avoid becoming more traffic statistics.”
Research reported in this publication was supported by Genentech, a member of the Roche Group, and a grant from the National Institute on Aging of the National Institutes of Health. Dr. Mattke reported receiving grants from Genentech for a research contract with USC during the conduct of the study; personal fees from Eisai, Biogen, C2N, Novo Nordisk, Novartis, and Roche Genentech; and serving on the Senscio Systems board of directors, ALZpath scientific advisory board, AiCure scientific advisory board, and Boston Millennia Partners scientific advisory board outside the submitted work. The other authors’ disclosures are listed on the original paper. The editorial was supported by the Canada Research Chair in Medical Decision Sciences, the Canadian Institutes of Health Research, Kimel-Schatzky Traumatic Brain Injury Research Fund, and the Graduate Diploma Program in Health Research at the University of Toronto. The editorial authors report no other relevant financial relationships.
A version of this article appeared on Medscape.com.
, new research suggests.
Investigators found that primary care physicians (PCPs) in states with clinician reporting mandates had a 59% higher probability of underdiagnosing dementia compared with their counterparts in states that require patients to self-report or that have no reporting mandates.
“Our findings in this cross-sectional study raise concerns about potential adverse effects of mandatory clinician reporting for dementia diagnosis and underscore the need for careful consideration of the effect of such policies,” wrote the investigators, led by Soeren Mattke, MD, DSc, director of the USC Brain Health Observatory and research professor of economics at the University of Southern California, Los Angeles.
The study was published online in JAMA Network Open.
Lack of Guidance
As the US population ages, the number of older drivers is increasing, with 55.8 million drivers 65 years old or older. Approximately 7 million people in this age group have dementia — an estimate that is expected to increase to nearly 12 million by 2040.
The aging population raises a “critical policy question” about how to ensure road safety. Although the American Medical Association’s Code of Ethics outlines a physician’s obligation to identify drivers with medical impairments that impede safe driving, guidance restricting cognitively impaired drivers from driving is lacking.
In addition, evidence as to whether cognitive impairment indeed poses a threat to driving safety is mixed and has led to a lack of uniform policies with respect to reporting dementia.
Four states explicitly require clinicians to report dementia diagnoses to the DMV, which will then determine the patient’s fitness to drive, whereas 14 states require people with dementia to self-report. The remaining states have no explicit reporting requirements.
The issue of mandatory reporting is controversial, the researchers noted. On the one hand, physicians could protect patients and others by reporting potentially unsafe drivers.
On the other hand, evidence of an association with lower accident risks in patients with dementia is sparse and mandatory reporting may adversely affect physician-patient relationships. Empirical evidence for unintended consequences of reporting laws is lacking.
To examine the potential link between dementia underdiagnosis and mandatory reporting policies, the investigators analyzed the 100% data from the Medicare fee-for-service program and Medicare Advantage plans from 2017 to 2019, which included 223,036 PCPs with a panel of 25 or more Medicare patients.
The researchers examined dementia diagnosis rates in the patient panel of PCPs, rather than neurologists or gerontologists, regardless of who documented the diagnosis. Dr. Mattke said that it is possible that the diagnosis was established after referral to a specialist.
Each physician’s expected number of dementia cases was estimated using a predictive model based on patient characteristics. The researchers then compared the estimate with observed dementia diagnoses, thereby identifying clinicians who underdiagnosed dementia after sampling errors were accounted for.
‘Heavy-Handed Interference’
The researchers adjusted for several covariates potentially associated with a clinician’s probability of underdiagnosing dementia. These included sex, office location, practice specialty, racial/ethnic composition of the patient panel, and percentage of patients dually eligible for Medicare and Medicaid. The table shows PCP characteristics.
Adjusted results showed that PCPs practicing in states with clinician reporting mandates had a 12.4% (95% confidence interval [CI], 10.5%-14.2%) probability of underdiagnosing dementia versus 7.8% (95% CI, 6.9%-8.7%) in states with self-reporting and 7.7% (95% CI, 6.9%-8.4%) in states with no mandates, translating into a 4–percentage point difference (P < .001).
“Our study is the first to provide empirical evidence for the potential adverse effects of reporting policies,” the researchers noted. “Although we found that some clinicians underdiagnosed dementia regardless of state mandates, the key finding of this study reveals that primary care clinicians who practice in states with clinician reporting mandates were 59% more likely to do so…compared with those states with no reporting requirements…or driver self-reporting requirements.”
The investigators suggested that one potential explanation for underdiagnosis is patient resistance to cognitive testing. If patients were aware that the clinician was obligated by law to report their dementia diagnosis to the DMV, “they might be more inclined to conceal their symptoms or refuse further assessments, in addition to the general stigma and resistance to a formal assessment after a positive dementia screening result.”
“The findings suggest that policymakers might want to rethink those physician reporting mandates, since we also could not find conclusive evidence that they improve road safety,” Dr. Mattke said. “Maybe patients and their physicians can arrive at a sensible approach to determine driving fitness without such heavy-handed interference.”
However, he cautioned that the findings are not definitive and further study is needed before firm recommendations either for or against mandatory reporting.
In addition, the researchers noted several study limitations. One is that dementia underdiagnosis may also be associated with factors not captured in their model, including physician-patient relationships, health literacy, or language barriers.
However, Dr. Mattke noted, “ my sense is that those unobservable factors are not systematically related to state reporting policies and having omitted them would therefore not bias our results.”
Experts Weigh In
Commenting on the research, Morgan Daven, MA, the Alzheimer’s Association vice president of health systems, said that dementia is widely and significantly underdiagnosed, and not only in the states with dementia reporting mandates. Many factors may contribute to underdiagnosis, and although the study shows an association between reporting mandates and underdiagnosis, it does not demonstrate causation.
That said, Mr. Daven added, “fear and stigma related to dementia may inhibit the clinician, the patient, and their family from pursuing detection and diagnosis for dementia. As a society, we need to address dementia fear and stigma for all parties.”
He noted that useful tools include healthcare policies, workforce training, public awareness and education, and public policies to mitigate fear and stigma and their negative effects on diagnosis, care, support, and communication.
A potential study limitation is that it relied only on diagnoses by PCPs. Mr. Daven noted that the diagnosis of Alzheimer’ disease — the most common cause of dementia — is confirmation of amyloid buildup via a biomarker test, using PET or cerebrospinal fluid analysis.
“Both of these tests are extremely limited in their use and accessibility in a primary care setting. Inclusion of diagnoses by dementia specialists would provide a more complete picture,” he said.
Mr. Daven added that the Alzheimer’s Association encourages families to proactively discuss driving and other disease-related safety concerns as soon as possible. The Alzheimer’s Association Dementia and Driving webpage offers tips and strategies to discuss driving concerns with a family member.
In an accompanying editorial, Donald Redelmeier, MD, MS(HSR), and Vidhi Bhatt, BSc, both of the Department of Medicine, University of Toronto, differentiate the mandate for physicians to warn patients with dementia about traffic safety from the mandate for reporting child maltreatment, gunshot victims, or communicable diseases. They noted that mandated warnings “are not easy, can engender patient dissatisfaction, and need to be handled with tact.”
Yet, they pointed out, “breaking bad news is what practicing medicine entails.” They emphasized that, regardless of government mandates, “counseling patients for more road safety is an essential skill for clinicians in diverse states who hope to help their patients avoid becoming more traffic statistics.”
Research reported in this publication was supported by Genentech, a member of the Roche Group, and a grant from the National Institute on Aging of the National Institutes of Health. Dr. Mattke reported receiving grants from Genentech for a research contract with USC during the conduct of the study; personal fees from Eisai, Biogen, C2N, Novo Nordisk, Novartis, and Roche Genentech; and serving on the Senscio Systems board of directors, ALZpath scientific advisory board, AiCure scientific advisory board, and Boston Millennia Partners scientific advisory board outside the submitted work. The other authors’ disclosures are listed on the original paper. The editorial was supported by the Canada Research Chair in Medical Decision Sciences, the Canadian Institutes of Health Research, Kimel-Schatzky Traumatic Brain Injury Research Fund, and the Graduate Diploma Program in Health Research at the University of Toronto. The editorial authors report no other relevant financial relationships.
A version of this article appeared on Medscape.com.
, new research suggests.
Investigators found that primary care physicians (PCPs) in states with clinician reporting mandates had a 59% higher probability of underdiagnosing dementia compared with their counterparts in states that require patients to self-report or that have no reporting mandates.
“Our findings in this cross-sectional study raise concerns about potential adverse effects of mandatory clinician reporting for dementia diagnosis and underscore the need for careful consideration of the effect of such policies,” wrote the investigators, led by Soeren Mattke, MD, DSc, director of the USC Brain Health Observatory and research professor of economics at the University of Southern California, Los Angeles.
The study was published online in JAMA Network Open.
Lack of Guidance
As the US population ages, the number of older drivers is increasing, with 55.8 million drivers 65 years old or older. Approximately 7 million people in this age group have dementia — an estimate that is expected to increase to nearly 12 million by 2040.
The aging population raises a “critical policy question” about how to ensure road safety. Although the American Medical Association’s Code of Ethics outlines a physician’s obligation to identify drivers with medical impairments that impede safe driving, guidance restricting cognitively impaired drivers from driving is lacking.
In addition, evidence as to whether cognitive impairment indeed poses a threat to driving safety is mixed and has led to a lack of uniform policies with respect to reporting dementia.
Four states explicitly require clinicians to report dementia diagnoses to the DMV, which will then determine the patient’s fitness to drive, whereas 14 states require people with dementia to self-report. The remaining states have no explicit reporting requirements.
The issue of mandatory reporting is controversial, the researchers noted. On the one hand, physicians could protect patients and others by reporting potentially unsafe drivers.
On the other hand, evidence of an association with lower accident risks in patients with dementia is sparse and mandatory reporting may adversely affect physician-patient relationships. Empirical evidence for unintended consequences of reporting laws is lacking.
To examine the potential link between dementia underdiagnosis and mandatory reporting policies, the investigators analyzed the 100% data from the Medicare fee-for-service program and Medicare Advantage plans from 2017 to 2019, which included 223,036 PCPs with a panel of 25 or more Medicare patients.
The researchers examined dementia diagnosis rates in the patient panel of PCPs, rather than neurologists or gerontologists, regardless of who documented the diagnosis. Dr. Mattke said that it is possible that the diagnosis was established after referral to a specialist.
Each physician’s expected number of dementia cases was estimated using a predictive model based on patient characteristics. The researchers then compared the estimate with observed dementia diagnoses, thereby identifying clinicians who underdiagnosed dementia after sampling errors were accounted for.
‘Heavy-Handed Interference’
The researchers adjusted for several covariates potentially associated with a clinician’s probability of underdiagnosing dementia. These included sex, office location, practice specialty, racial/ethnic composition of the patient panel, and percentage of patients dually eligible for Medicare and Medicaid. The table shows PCP characteristics.
Adjusted results showed that PCPs practicing in states with clinician reporting mandates had a 12.4% (95% confidence interval [CI], 10.5%-14.2%) probability of underdiagnosing dementia versus 7.8% (95% CI, 6.9%-8.7%) in states with self-reporting and 7.7% (95% CI, 6.9%-8.4%) in states with no mandates, translating into a 4–percentage point difference (P < .001).
“Our study is the first to provide empirical evidence for the potential adverse effects of reporting policies,” the researchers noted. “Although we found that some clinicians underdiagnosed dementia regardless of state mandates, the key finding of this study reveals that primary care clinicians who practice in states with clinician reporting mandates were 59% more likely to do so…compared with those states with no reporting requirements…or driver self-reporting requirements.”
The investigators suggested that one potential explanation for underdiagnosis is patient resistance to cognitive testing. If patients were aware that the clinician was obligated by law to report their dementia diagnosis to the DMV, “they might be more inclined to conceal their symptoms or refuse further assessments, in addition to the general stigma and resistance to a formal assessment after a positive dementia screening result.”
“The findings suggest that policymakers might want to rethink those physician reporting mandates, since we also could not find conclusive evidence that they improve road safety,” Dr. Mattke said. “Maybe patients and their physicians can arrive at a sensible approach to determine driving fitness without such heavy-handed interference.”
However, he cautioned that the findings are not definitive and further study is needed before firm recommendations either for or against mandatory reporting.
In addition, the researchers noted several study limitations. One is that dementia underdiagnosis may also be associated with factors not captured in their model, including physician-patient relationships, health literacy, or language barriers.
However, Dr. Mattke noted, “ my sense is that those unobservable factors are not systematically related to state reporting policies and having omitted them would therefore not bias our results.”
Experts Weigh In
Commenting on the research, Morgan Daven, MA, the Alzheimer’s Association vice president of health systems, said that dementia is widely and significantly underdiagnosed, and not only in the states with dementia reporting mandates. Many factors may contribute to underdiagnosis, and although the study shows an association between reporting mandates and underdiagnosis, it does not demonstrate causation.
That said, Mr. Daven added, “fear and stigma related to dementia may inhibit the clinician, the patient, and their family from pursuing detection and diagnosis for dementia. As a society, we need to address dementia fear and stigma for all parties.”
He noted that useful tools include healthcare policies, workforce training, public awareness and education, and public policies to mitigate fear and stigma and their negative effects on diagnosis, care, support, and communication.
A potential study limitation is that it relied only on diagnoses by PCPs. Mr. Daven noted that the diagnosis of Alzheimer’ disease — the most common cause of dementia — is confirmation of amyloid buildup via a biomarker test, using PET or cerebrospinal fluid analysis.
“Both of these tests are extremely limited in their use and accessibility in a primary care setting. Inclusion of diagnoses by dementia specialists would provide a more complete picture,” he said.
Mr. Daven added that the Alzheimer’s Association encourages families to proactively discuss driving and other disease-related safety concerns as soon as possible. The Alzheimer’s Association Dementia and Driving webpage offers tips and strategies to discuss driving concerns with a family member.
In an accompanying editorial, Donald Redelmeier, MD, MS(HSR), and Vidhi Bhatt, BSc, both of the Department of Medicine, University of Toronto, differentiate the mandate for physicians to warn patients with dementia about traffic safety from the mandate for reporting child maltreatment, gunshot victims, or communicable diseases. They noted that mandated warnings “are not easy, can engender patient dissatisfaction, and need to be handled with tact.”
Yet, they pointed out, “breaking bad news is what practicing medicine entails.” They emphasized that, regardless of government mandates, “counseling patients for more road safety is an essential skill for clinicians in diverse states who hope to help their patients avoid becoming more traffic statistics.”
Research reported in this publication was supported by Genentech, a member of the Roche Group, and a grant from the National Institute on Aging of the National Institutes of Health. Dr. Mattke reported receiving grants from Genentech for a research contract with USC during the conduct of the study; personal fees from Eisai, Biogen, C2N, Novo Nordisk, Novartis, and Roche Genentech; and serving on the Senscio Systems board of directors, ALZpath scientific advisory board, AiCure scientific advisory board, and Boston Millennia Partners scientific advisory board outside the submitted work. The other authors’ disclosures are listed on the original paper. The editorial was supported by the Canada Research Chair in Medical Decision Sciences, the Canadian Institutes of Health Research, Kimel-Schatzky Traumatic Brain Injury Research Fund, and the Graduate Diploma Program in Health Research at the University of Toronto. The editorial authors report no other relevant financial relationships.
A version of this article appeared on Medscape.com.
From JAMA Network Open
Does ‘Brain Training’ Really Improve Cognition and Forestall Cognitive Decline?
The concept that cognitive health can be preserved or improved is often expressed as “use it or lose it.” Numerous modifiable risk factors are associated with “losing” cognitive abilities with age, and a cognitively active lifestyle may have a protective effect.
But what is a “cognitively active lifestyle” — do crosswords and Sudoku count?
One popular approach is “brain training.” While not a scientific term with an established definition, it “typically refers to tasks or drills that are designed to strengthen specific aspects of one’s cognitive function,” explained Yuko Hara, PhD, director of Aging and Alzheimer’s Prevention at the Alzheimer’s Drug Discovery Foundation.
Manuel Montero-Odasso, MD, PhD, director of the Gait and Brain Lab, Parkwood Institute, London, Ontario, Canada, elaborated: “Cognitive training involves performing a definitive task or set of tasks where you increase attentional demands to improve focus and concentration and memory. You try to execute the new things that you’ve learned and to remember them.”
In a commentary published by this news organization in 2022, neuroscientist Michael Merzenich, PhD, professor emeritus at University of California San Francisco, said that growing a person’s cognitive reserve and actively managing brain health can play an important role in preventing or delaying Alzheimer’s disease. Important components of this include brain training and physical exercise.
Brain Training: Mechanism of Action
Dr. Montero-Odasso, team leader at the Canadian Consortium on Neurodegeneration in Aging and team co-leader at the Ontario Neurodegenerative Research Initiative, explained that cognitive training creates new synapses in the brain, thus stimulating neuroplasticity.
“When we try to activate networks mainly in the frontal lobe, the prefrontal cortex, a key mechanism underlying this process is enhancement of the synaptic plasticity at excitatory synapses, which connect neurons into networks; in other words, we generate new synapses, and that’s how we enhance brain health and cognitive abilities.”
The more neural connections, the greater the processing speed of the brain, he continued. “Cognitive training creates an anatomical change in the brain.”
Executive functions, which include attention, inhibition, planning, and multitasking, are regulated predominantly by the prefrontal cortex. Damage in this region of the brain is also implicated in dementia. Alterations in the connectivity of this area are associated with cognitive impairment, independent of other structural pathological aberrations (eg, gray matter atrophy). These patterns may precede structural pathological changes associated with cognitive impairment and dementia.
Neuroplasticity changes have been corroborated through neuroimaging, which has demonstrated that after cognitive training, there is more activation in the prefrontal cortex that correlates with new synapses, Dr. Montero-Odasso said.
Henry Mahncke, PhD, CEO of the brain training company Posit Science/BrainHQ, explained that early research was conducted on rodents and monkeys, with Dr. Merzenich as one of the leading pioneers in developing the concept of brain plasticity. Dr. Merzenich cofounded Posit Science and is currently its chief scientific officer.
Dr. Mahncke recounted that as a graduate student, he had worked with Dr. Merzenich researching brain plasticity. When Dr. Merzenich founded Posit Science, he asked Dr. Mahncke to join the company to help develop approaches to enhance brain plasticity — building the brain-training exercises and running the clinical trials.
“It’s now well understood that the brain can rewire itself at any age and in almost any condition,” Dr. Mahncke said. “In kids and in younger and older adults, whether with healthy or unhealthy brains, the fundamental way the brain works is by continually rewiring and rebuilding itself, based on what we ask it to do.”
Dr. Mahncke said.
Unsubstantiated Claims and Controversy
Brain training is not without controversy, Dr. Hara pointed out. “Some manufacturers of brain games have been criticized and even fined for making unsubstantiated claims,” she said.
A 2016 review found that brain-training interventions do improve performance on specific trained tasks, but there is less evidence that they improve performance on closely related tasks and little evidence that training improves everyday cognitive performance. A 2017 review reached similar conclusions, calling evidence regarding prevention or delay of cognitive decline or dementia through brain games “insufficient,” although cognitive training could “improve cognition in the domain trained.”
“The general consensus is that for most brain-training programs, people may get better at specific tasks through practice, but these improvements don’t necessarily translate into improvement in other tasks that require other cognitive domains or prevention of dementia or age-related cognitive decline,” Dr. Hara said.
She noted that most brain-training programs “have not been rigorously tested in clinical trials” — although some, such as those featured in the ACTIVE trial, did show evidence of effectiveness.
Dr. Mahncke agreed. “Asking whether brain training works is like asking whether small molecules improve health,” he said noting that some brain-training programs are nonsense and not evidence based. He believes that his company’s product, BrainHQ, and some others are “backed by robust evidence in their ability to stave off, slow, or even reverse cognitive changes.”
BrainHQ is a web-based brain game suite that can be used independently as an app or in group settings (classes and webinars) and is covered by some Medicare Advantage insurance plans. It encompasses “dozens of individual brain-training exercises, linked by a common thread. Each one is intensively designed to make the brain faster and more accurate,” said Dr. Mahncke.
He explained that human brains “get noisy as people get older, like a radio which is wearing out, so there’s static in the background. This makes the music hard to hear, and in the case of the human brain, it makes it difficult to pay attention.” The exercises are “designed to tamp down the ‘noise,’ speed up the brain, and make information processing more accurate.”
Dr. Mahncke called this a “bottom-up” approach, in contrast to many previous cognitive-training approaches that come from the brain injury rehabilitation field. They teach “top-down” skills and strategies designed to compensate for deficits in specific domains, such as reading, concentration, or fine motor skills.
By contrast, the approach of BrainHQ is “to improve the overall processing system of the brain with speed, attention, working memory, and executive function, which will in turn impact all skills and activities.”
Supporting Evidence
Dr. Mahncke cited several supporting studies. For example, the IMPACT study randomized 487 adults (aged ≥ 65 years) to receive either a brain plasticity–based computerized cognitive training program (BrainHQ) or a novelty- and intensity-matched general cognitive stimulation treatment program (intervention and control group, respectively) for an 8-week period.
Those who underwent brain training showed significantly greater improvement in the repeatable Battery for the Assessment of Neuropsychological Status (RBANS Auditory Memory/Attention) compared with those in the control group (3.9 vs 1.8, respectively; P =.02). The intervention group also showed significant improvements on multiple secondary measures of attention and memory. The magnitude of the effect sizes suggests that the results are clinically significant, according to the authors.
The ACTIVE study tested the effects of different cognitive training programs on cognitive function and time to dementia. The researchers randomized 2802 healthy older adults (mean age, 74 years) to a control group with no cognitive training or one of three brain-training groups comprising:
1. In-person training on verbal memory skills
2. In-person training on reasoning and problem-solving
3. Computer-based speed-of-processing training on visual attention
Participants in the training groups completed 10 sessions, each lasting 60-75 minutes, over a 5- to 6-week period. A random subsample of each training group was selected to receive “booster” sessions, with four-session booster training delivered at 11 and 35 months. All study participants completed follow-up tests of cognition and function after 1, 2, 3, 5, and 10 years.
At the end of 10 years, those assigned to the speed-of-processing training, now part of BrainHQ, had a 29% lower risk for dementia than those in the control group who received no training. No reduction was found in the memory or reasoning training groups. Participants who completed the “booster” sessions had an even greater reduction: Each additional booster session was associated with a 10% lower risk for dementia.
Dr. Montero-Odasso was involved in the SYNERGIC study that randomized 175 participants with mild cognitive impairment (MCI; average age, 73 years) to one of five study arms:
1. Multidomain intervention with exercise, cognitive training, and vitamin D
2. Exercise, cognitive training, and placebo
3. Exercise, sham cognitive training, and vitamin D
4. Exercise, sham cognitive training, and placebo
5. Control group with balance-toning exercise, sham cognitive training, and placebo
“Sham” cognitive training consisted of alternating between two tasks (touristic search and video watching) performed on a tablet, with the same time exposure as the intervention training.
The researchers found that after 6 months of interventions, all active arms with aerobic-resistance exercise showed improvement in the ADAS-Cog-13, an established outcome to evaluate dementia treatments, when compared with the control group — regardless of the addition of cognitive training or vitamin D.
Compared with exercise alone (arms 3 and 4), those who did exercise plus cognitive training (arms 1 and 2) showed greater improvements in their ADAS-Cog-13l score, with a mean difference of −1.45 points (P = .02). The greatest improvement was seen in those who underwent the multidomain intervention in arm 1.
The authors noted that the mean 2.64-point improvement seen in the ADAS-Cog-13 for the multidomain intervention is actually larger than changes seen in previous pharmaceutical trials among individuals with MCI or mild dementia and “approaches” the three points considered clinically meaningful.
“We found that older adults with MCI who received aerobic-resistance exercise with sequential computerized cognitive training significantly improved cognition,” Dr. Montero-Odasso said. “The cognitive training we used was called Neuropeak, a multidomain lifestyle training delivered through a web-based platform developed by our co-leader Louis Bherer at Université de Montréal.”
He explained that the purpose “is to challenge your brain to the point where you need to make an effort to remember things, pay attention, and later to execute tasks. The evidence from clinical trials, including ours, shows this type of brain challenge is effective in slowing and even reversing cognitive decline.”
A follow-up study, SYNERGIC 2.0, is ongoing.
Puzzles, Board Games, and New Challenges
Formal brain-training programs aren’t the only way to improve brain plasticity, Dr. Hara said. Observational studies suggested an association between improved cognitive performance and/or lower dementia risk and engaging in number and word puzzles, such as crosswords, cards, or board games.
Some studies suggested that older adults who use technology might also protect their cognitive reserve. Dr. Hara cited a US longitudinal study of more than 18,000 older adults suggesting that regular Internet users had roughly half the risk for dementia compared to nonregular Internet users. Estimates of daily Internet use suggested a U-shaped relationship with dementia with 0.1-2.0 hours daily (excluding time spent watching television or movies online) associated with the lowest risk. Similar associations between Internet use and a lower risk for cognitive decline have been reported in the United Kingdom and Europe.
“Engaging in mentally stimulating activities can increase ‘cognitive reserve’ — meaning, capacity of the brain to resist the effects of age-related changes or disease-related pathology, such that one can maintain cognitive function for longer,” Dr. Hara said. “Cognitively stimulating activities, regardless of the type, may help delay the onset of cognitive decline.”
She listed several examples of activities that are stimulating to the brain, including learning a new game or puzzle, a new language, or a new dance, and learning how to play a musical instrument.
Dr. Montero-Odasso emphasized that the “newness” is key to increasing and preserving cognitive reserve. “Just surfing the Internet, playing word or board games, or doing crossword puzzles won’t be enough if you’ve been doing these things all your life,” he said. “It won’t hurt, of course, but it won’t necessarily increase your cognitive abilities.
“For example, a person who regularly engages in public speaking may not improve cognition by taking a public-speaking course, but someone who has never spoken before an audience might show cognitive improvements as a result of learning a new skill,” he said. “Or someone who knows several languages already might gain from learning a brand-new language.”
He cited research supporting the benefits of dancing, which he called “an ideal activity because it’s physical, so it provides the exercise that’s been associated with improved cognition. But it also requires learning new steps and moves, which builds the synapses in the brain. And the socialization of dance classes adds another component that can improve cognition.”
Dr. Mahncke hopes that beyond engaging in day-to-day new activities, seniors will participate in computerized brain training. “There’s no reason that evidence-based training can’t be offered in senior and community centers, as yoga and swimming are,” he said. “It doesn’t have to be simply something people do on their own virtually.”
Zoom classes and Medicare reimbursements are “good steps in the right direction, but it’s time to expand this potentially life-transformative intervention so that it reaches the ever-expanding population of seniors in the United States and beyond.”
Dr. Hara reported having no disclosures. Dr. Montero-Odasso reported having no commercial or financial interest related to this topic. He serves as the president of the Canadian Geriatrics Société and is team leader in the Canadian Consortium of Neurodegeneration in Aging. Dr. Mahncke is CEO of the brain training company Posit Science/BrainHQ.
A version of this article appeared on Medscape.com.
The concept that cognitive health can be preserved or improved is often expressed as “use it or lose it.” Numerous modifiable risk factors are associated with “losing” cognitive abilities with age, and a cognitively active lifestyle may have a protective effect.
But what is a “cognitively active lifestyle” — do crosswords and Sudoku count?
One popular approach is “brain training.” While not a scientific term with an established definition, it “typically refers to tasks or drills that are designed to strengthen specific aspects of one’s cognitive function,” explained Yuko Hara, PhD, director of Aging and Alzheimer’s Prevention at the Alzheimer’s Drug Discovery Foundation.
Manuel Montero-Odasso, MD, PhD, director of the Gait and Brain Lab, Parkwood Institute, London, Ontario, Canada, elaborated: “Cognitive training involves performing a definitive task or set of tasks where you increase attentional demands to improve focus and concentration and memory. You try to execute the new things that you’ve learned and to remember them.”
In a commentary published by this news organization in 2022, neuroscientist Michael Merzenich, PhD, professor emeritus at University of California San Francisco, said that growing a person’s cognitive reserve and actively managing brain health can play an important role in preventing or delaying Alzheimer’s disease. Important components of this include brain training and physical exercise.
Brain Training: Mechanism of Action
Dr. Montero-Odasso, team leader at the Canadian Consortium on Neurodegeneration in Aging and team co-leader at the Ontario Neurodegenerative Research Initiative, explained that cognitive training creates new synapses in the brain, thus stimulating neuroplasticity.
“When we try to activate networks mainly in the frontal lobe, the prefrontal cortex, a key mechanism underlying this process is enhancement of the synaptic plasticity at excitatory synapses, which connect neurons into networks; in other words, we generate new synapses, and that’s how we enhance brain health and cognitive abilities.”
The more neural connections, the greater the processing speed of the brain, he continued. “Cognitive training creates an anatomical change in the brain.”
Executive functions, which include attention, inhibition, planning, and multitasking, are regulated predominantly by the prefrontal cortex. Damage in this region of the brain is also implicated in dementia. Alterations in the connectivity of this area are associated with cognitive impairment, independent of other structural pathological aberrations (eg, gray matter atrophy). These patterns may precede structural pathological changes associated with cognitive impairment and dementia.
Neuroplasticity changes have been corroborated through neuroimaging, which has demonstrated that after cognitive training, there is more activation in the prefrontal cortex that correlates with new synapses, Dr. Montero-Odasso said.
Henry Mahncke, PhD, CEO of the brain training company Posit Science/BrainHQ, explained that early research was conducted on rodents and monkeys, with Dr. Merzenich as one of the leading pioneers in developing the concept of brain plasticity. Dr. Merzenich cofounded Posit Science and is currently its chief scientific officer.
Dr. Mahncke recounted that as a graduate student, he had worked with Dr. Merzenich researching brain plasticity. When Dr. Merzenich founded Posit Science, he asked Dr. Mahncke to join the company to help develop approaches to enhance brain plasticity — building the brain-training exercises and running the clinical trials.
“It’s now well understood that the brain can rewire itself at any age and in almost any condition,” Dr. Mahncke said. “In kids and in younger and older adults, whether with healthy or unhealthy brains, the fundamental way the brain works is by continually rewiring and rebuilding itself, based on what we ask it to do.”
Dr. Mahncke said.
Unsubstantiated Claims and Controversy
Brain training is not without controversy, Dr. Hara pointed out. “Some manufacturers of brain games have been criticized and even fined for making unsubstantiated claims,” she said.
A 2016 review found that brain-training interventions do improve performance on specific trained tasks, but there is less evidence that they improve performance on closely related tasks and little evidence that training improves everyday cognitive performance. A 2017 review reached similar conclusions, calling evidence regarding prevention or delay of cognitive decline or dementia through brain games “insufficient,” although cognitive training could “improve cognition in the domain trained.”
“The general consensus is that for most brain-training programs, people may get better at specific tasks through practice, but these improvements don’t necessarily translate into improvement in other tasks that require other cognitive domains or prevention of dementia or age-related cognitive decline,” Dr. Hara said.
She noted that most brain-training programs “have not been rigorously tested in clinical trials” — although some, such as those featured in the ACTIVE trial, did show evidence of effectiveness.
Dr. Mahncke agreed. “Asking whether brain training works is like asking whether small molecules improve health,” he said noting that some brain-training programs are nonsense and not evidence based. He believes that his company’s product, BrainHQ, and some others are “backed by robust evidence in their ability to stave off, slow, or even reverse cognitive changes.”
BrainHQ is a web-based brain game suite that can be used independently as an app or in group settings (classes and webinars) and is covered by some Medicare Advantage insurance plans. It encompasses “dozens of individual brain-training exercises, linked by a common thread. Each one is intensively designed to make the brain faster and more accurate,” said Dr. Mahncke.
He explained that human brains “get noisy as people get older, like a radio which is wearing out, so there’s static in the background. This makes the music hard to hear, and in the case of the human brain, it makes it difficult to pay attention.” The exercises are “designed to tamp down the ‘noise,’ speed up the brain, and make information processing more accurate.”
Dr. Mahncke called this a “bottom-up” approach, in contrast to many previous cognitive-training approaches that come from the brain injury rehabilitation field. They teach “top-down” skills and strategies designed to compensate for deficits in specific domains, such as reading, concentration, or fine motor skills.
By contrast, the approach of BrainHQ is “to improve the overall processing system of the brain with speed, attention, working memory, and executive function, which will in turn impact all skills and activities.”
Supporting Evidence
Dr. Mahncke cited several supporting studies. For example, the IMPACT study randomized 487 adults (aged ≥ 65 years) to receive either a brain plasticity–based computerized cognitive training program (BrainHQ) or a novelty- and intensity-matched general cognitive stimulation treatment program (intervention and control group, respectively) for an 8-week period.
Those who underwent brain training showed significantly greater improvement in the repeatable Battery for the Assessment of Neuropsychological Status (RBANS Auditory Memory/Attention) compared with those in the control group (3.9 vs 1.8, respectively; P =.02). The intervention group also showed significant improvements on multiple secondary measures of attention and memory. The magnitude of the effect sizes suggests that the results are clinically significant, according to the authors.
The ACTIVE study tested the effects of different cognitive training programs on cognitive function and time to dementia. The researchers randomized 2802 healthy older adults (mean age, 74 years) to a control group with no cognitive training or one of three brain-training groups comprising:
1. In-person training on verbal memory skills
2. In-person training on reasoning and problem-solving
3. Computer-based speed-of-processing training on visual attention
Participants in the training groups completed 10 sessions, each lasting 60-75 minutes, over a 5- to 6-week period. A random subsample of each training group was selected to receive “booster” sessions, with four-session booster training delivered at 11 and 35 months. All study participants completed follow-up tests of cognition and function after 1, 2, 3, 5, and 10 years.
At the end of 10 years, those assigned to the speed-of-processing training, now part of BrainHQ, had a 29% lower risk for dementia than those in the control group who received no training. No reduction was found in the memory or reasoning training groups. Participants who completed the “booster” sessions had an even greater reduction: Each additional booster session was associated with a 10% lower risk for dementia.
Dr. Montero-Odasso was involved in the SYNERGIC study that randomized 175 participants with mild cognitive impairment (MCI; average age, 73 years) to one of five study arms:
1. Multidomain intervention with exercise, cognitive training, and vitamin D
2. Exercise, cognitive training, and placebo
3. Exercise, sham cognitive training, and vitamin D
4. Exercise, sham cognitive training, and placebo
5. Control group with balance-toning exercise, sham cognitive training, and placebo
“Sham” cognitive training consisted of alternating between two tasks (touristic search and video watching) performed on a tablet, with the same time exposure as the intervention training.
The researchers found that after 6 months of interventions, all active arms with aerobic-resistance exercise showed improvement in the ADAS-Cog-13, an established outcome to evaluate dementia treatments, when compared with the control group — regardless of the addition of cognitive training or vitamin D.
Compared with exercise alone (arms 3 and 4), those who did exercise plus cognitive training (arms 1 and 2) showed greater improvements in their ADAS-Cog-13l score, with a mean difference of −1.45 points (P = .02). The greatest improvement was seen in those who underwent the multidomain intervention in arm 1.
The authors noted that the mean 2.64-point improvement seen in the ADAS-Cog-13 for the multidomain intervention is actually larger than changes seen in previous pharmaceutical trials among individuals with MCI or mild dementia and “approaches” the three points considered clinically meaningful.
“We found that older adults with MCI who received aerobic-resistance exercise with sequential computerized cognitive training significantly improved cognition,” Dr. Montero-Odasso said. “The cognitive training we used was called Neuropeak, a multidomain lifestyle training delivered through a web-based platform developed by our co-leader Louis Bherer at Université de Montréal.”
He explained that the purpose “is to challenge your brain to the point where you need to make an effort to remember things, pay attention, and later to execute tasks. The evidence from clinical trials, including ours, shows this type of brain challenge is effective in slowing and even reversing cognitive decline.”
A follow-up study, SYNERGIC 2.0, is ongoing.
Puzzles, Board Games, and New Challenges
Formal brain-training programs aren’t the only way to improve brain plasticity, Dr. Hara said. Observational studies suggested an association between improved cognitive performance and/or lower dementia risk and engaging in number and word puzzles, such as crosswords, cards, or board games.
Some studies suggested that older adults who use technology might also protect their cognitive reserve. Dr. Hara cited a US longitudinal study of more than 18,000 older adults suggesting that regular Internet users had roughly half the risk for dementia compared to nonregular Internet users. Estimates of daily Internet use suggested a U-shaped relationship with dementia with 0.1-2.0 hours daily (excluding time spent watching television or movies online) associated with the lowest risk. Similar associations between Internet use and a lower risk for cognitive decline have been reported in the United Kingdom and Europe.
“Engaging in mentally stimulating activities can increase ‘cognitive reserve’ — meaning, capacity of the brain to resist the effects of age-related changes or disease-related pathology, such that one can maintain cognitive function for longer,” Dr. Hara said. “Cognitively stimulating activities, regardless of the type, may help delay the onset of cognitive decline.”
She listed several examples of activities that are stimulating to the brain, including learning a new game or puzzle, a new language, or a new dance, and learning how to play a musical instrument.
Dr. Montero-Odasso emphasized that the “newness” is key to increasing and preserving cognitive reserve. “Just surfing the Internet, playing word or board games, or doing crossword puzzles won’t be enough if you’ve been doing these things all your life,” he said. “It won’t hurt, of course, but it won’t necessarily increase your cognitive abilities.
“For example, a person who regularly engages in public speaking may not improve cognition by taking a public-speaking course, but someone who has never spoken before an audience might show cognitive improvements as a result of learning a new skill,” he said. “Or someone who knows several languages already might gain from learning a brand-new language.”
He cited research supporting the benefits of dancing, which he called “an ideal activity because it’s physical, so it provides the exercise that’s been associated with improved cognition. But it also requires learning new steps and moves, which builds the synapses in the brain. And the socialization of dance classes adds another component that can improve cognition.”
Dr. Mahncke hopes that beyond engaging in day-to-day new activities, seniors will participate in computerized brain training. “There’s no reason that evidence-based training can’t be offered in senior and community centers, as yoga and swimming are,” he said. “It doesn’t have to be simply something people do on their own virtually.”
Zoom classes and Medicare reimbursements are “good steps in the right direction, but it’s time to expand this potentially life-transformative intervention so that it reaches the ever-expanding population of seniors in the United States and beyond.”
Dr. Hara reported having no disclosures. Dr. Montero-Odasso reported having no commercial or financial interest related to this topic. He serves as the president of the Canadian Geriatrics Société and is team leader in the Canadian Consortium of Neurodegeneration in Aging. Dr. Mahncke is CEO of the brain training company Posit Science/BrainHQ.
A version of this article appeared on Medscape.com.
The concept that cognitive health can be preserved or improved is often expressed as “use it or lose it.” Numerous modifiable risk factors are associated with “losing” cognitive abilities with age, and a cognitively active lifestyle may have a protective effect.
But what is a “cognitively active lifestyle” — do crosswords and Sudoku count?
One popular approach is “brain training.” While not a scientific term with an established definition, it “typically refers to tasks or drills that are designed to strengthen specific aspects of one’s cognitive function,” explained Yuko Hara, PhD, director of Aging and Alzheimer’s Prevention at the Alzheimer’s Drug Discovery Foundation.
Manuel Montero-Odasso, MD, PhD, director of the Gait and Brain Lab, Parkwood Institute, London, Ontario, Canada, elaborated: “Cognitive training involves performing a definitive task or set of tasks where you increase attentional demands to improve focus and concentration and memory. You try to execute the new things that you’ve learned and to remember them.”
In a commentary published by this news organization in 2022, neuroscientist Michael Merzenich, PhD, professor emeritus at University of California San Francisco, said that growing a person’s cognitive reserve and actively managing brain health can play an important role in preventing or delaying Alzheimer’s disease. Important components of this include brain training and physical exercise.
Brain Training: Mechanism of Action
Dr. Montero-Odasso, team leader at the Canadian Consortium on Neurodegeneration in Aging and team co-leader at the Ontario Neurodegenerative Research Initiative, explained that cognitive training creates new synapses in the brain, thus stimulating neuroplasticity.
“When we try to activate networks mainly in the frontal lobe, the prefrontal cortex, a key mechanism underlying this process is enhancement of the synaptic plasticity at excitatory synapses, which connect neurons into networks; in other words, we generate new synapses, and that’s how we enhance brain health and cognitive abilities.”
The more neural connections, the greater the processing speed of the brain, he continued. “Cognitive training creates an anatomical change in the brain.”
Executive functions, which include attention, inhibition, planning, and multitasking, are regulated predominantly by the prefrontal cortex. Damage in this region of the brain is also implicated in dementia. Alterations in the connectivity of this area are associated with cognitive impairment, independent of other structural pathological aberrations (eg, gray matter atrophy). These patterns may precede structural pathological changes associated with cognitive impairment and dementia.
Neuroplasticity changes have been corroborated through neuroimaging, which has demonstrated that after cognitive training, there is more activation in the prefrontal cortex that correlates with new synapses, Dr. Montero-Odasso said.
Henry Mahncke, PhD, CEO of the brain training company Posit Science/BrainHQ, explained that early research was conducted on rodents and monkeys, with Dr. Merzenich as one of the leading pioneers in developing the concept of brain plasticity. Dr. Merzenich cofounded Posit Science and is currently its chief scientific officer.
Dr. Mahncke recounted that as a graduate student, he had worked with Dr. Merzenich researching brain plasticity. When Dr. Merzenich founded Posit Science, he asked Dr. Mahncke to join the company to help develop approaches to enhance brain plasticity — building the brain-training exercises and running the clinical trials.
“It’s now well understood that the brain can rewire itself at any age and in almost any condition,” Dr. Mahncke said. “In kids and in younger and older adults, whether with healthy or unhealthy brains, the fundamental way the brain works is by continually rewiring and rebuilding itself, based on what we ask it to do.”
Dr. Mahncke said.
Unsubstantiated Claims and Controversy
Brain training is not without controversy, Dr. Hara pointed out. “Some manufacturers of brain games have been criticized and even fined for making unsubstantiated claims,” she said.
A 2016 review found that brain-training interventions do improve performance on specific trained tasks, but there is less evidence that they improve performance on closely related tasks and little evidence that training improves everyday cognitive performance. A 2017 review reached similar conclusions, calling evidence regarding prevention or delay of cognitive decline or dementia through brain games “insufficient,” although cognitive training could “improve cognition in the domain trained.”
“The general consensus is that for most brain-training programs, people may get better at specific tasks through practice, but these improvements don’t necessarily translate into improvement in other tasks that require other cognitive domains or prevention of dementia or age-related cognitive decline,” Dr. Hara said.
She noted that most brain-training programs “have not been rigorously tested in clinical trials” — although some, such as those featured in the ACTIVE trial, did show evidence of effectiveness.
Dr. Mahncke agreed. “Asking whether brain training works is like asking whether small molecules improve health,” he said noting that some brain-training programs are nonsense and not evidence based. He believes that his company’s product, BrainHQ, and some others are “backed by robust evidence in their ability to stave off, slow, or even reverse cognitive changes.”
BrainHQ is a web-based brain game suite that can be used independently as an app or in group settings (classes and webinars) and is covered by some Medicare Advantage insurance plans. It encompasses “dozens of individual brain-training exercises, linked by a common thread. Each one is intensively designed to make the brain faster and more accurate,” said Dr. Mahncke.
He explained that human brains “get noisy as people get older, like a radio which is wearing out, so there’s static in the background. This makes the music hard to hear, and in the case of the human brain, it makes it difficult to pay attention.” The exercises are “designed to tamp down the ‘noise,’ speed up the brain, and make information processing more accurate.”
Dr. Mahncke called this a “bottom-up” approach, in contrast to many previous cognitive-training approaches that come from the brain injury rehabilitation field. They teach “top-down” skills and strategies designed to compensate for deficits in specific domains, such as reading, concentration, or fine motor skills.
By contrast, the approach of BrainHQ is “to improve the overall processing system of the brain with speed, attention, working memory, and executive function, which will in turn impact all skills and activities.”
Supporting Evidence
Dr. Mahncke cited several supporting studies. For example, the IMPACT study randomized 487 adults (aged ≥ 65 years) to receive either a brain plasticity–based computerized cognitive training program (BrainHQ) or a novelty- and intensity-matched general cognitive stimulation treatment program (intervention and control group, respectively) for an 8-week period.
Those who underwent brain training showed significantly greater improvement in the repeatable Battery for the Assessment of Neuropsychological Status (RBANS Auditory Memory/Attention) compared with those in the control group (3.9 vs 1.8, respectively; P =.02). The intervention group also showed significant improvements on multiple secondary measures of attention and memory. The magnitude of the effect sizes suggests that the results are clinically significant, according to the authors.
The ACTIVE study tested the effects of different cognitive training programs on cognitive function and time to dementia. The researchers randomized 2802 healthy older adults (mean age, 74 years) to a control group with no cognitive training or one of three brain-training groups comprising:
1. In-person training on verbal memory skills
2. In-person training on reasoning and problem-solving
3. Computer-based speed-of-processing training on visual attention
Participants in the training groups completed 10 sessions, each lasting 60-75 minutes, over a 5- to 6-week period. A random subsample of each training group was selected to receive “booster” sessions, with four-session booster training delivered at 11 and 35 months. All study participants completed follow-up tests of cognition and function after 1, 2, 3, 5, and 10 years.
At the end of 10 years, those assigned to the speed-of-processing training, now part of BrainHQ, had a 29% lower risk for dementia than those in the control group who received no training. No reduction was found in the memory or reasoning training groups. Participants who completed the “booster” sessions had an even greater reduction: Each additional booster session was associated with a 10% lower risk for dementia.
Dr. Montero-Odasso was involved in the SYNERGIC study that randomized 175 participants with mild cognitive impairment (MCI; average age, 73 years) to one of five study arms:
1. Multidomain intervention with exercise, cognitive training, and vitamin D
2. Exercise, cognitive training, and placebo
3. Exercise, sham cognitive training, and vitamin D
4. Exercise, sham cognitive training, and placebo
5. Control group with balance-toning exercise, sham cognitive training, and placebo
“Sham” cognitive training consisted of alternating between two tasks (touristic search and video watching) performed on a tablet, with the same time exposure as the intervention training.
The researchers found that after 6 months of interventions, all active arms with aerobic-resistance exercise showed improvement in the ADAS-Cog-13, an established outcome to evaluate dementia treatments, when compared with the control group — regardless of the addition of cognitive training or vitamin D.
Compared with exercise alone (arms 3 and 4), those who did exercise plus cognitive training (arms 1 and 2) showed greater improvements in their ADAS-Cog-13l score, with a mean difference of −1.45 points (P = .02). The greatest improvement was seen in those who underwent the multidomain intervention in arm 1.
The authors noted that the mean 2.64-point improvement seen in the ADAS-Cog-13 for the multidomain intervention is actually larger than changes seen in previous pharmaceutical trials among individuals with MCI or mild dementia and “approaches” the three points considered clinically meaningful.
“We found that older adults with MCI who received aerobic-resistance exercise with sequential computerized cognitive training significantly improved cognition,” Dr. Montero-Odasso said. “The cognitive training we used was called Neuropeak, a multidomain lifestyle training delivered through a web-based platform developed by our co-leader Louis Bherer at Université de Montréal.”
He explained that the purpose “is to challenge your brain to the point where you need to make an effort to remember things, pay attention, and later to execute tasks. The evidence from clinical trials, including ours, shows this type of brain challenge is effective in slowing and even reversing cognitive decline.”
A follow-up study, SYNERGIC 2.0, is ongoing.
Puzzles, Board Games, and New Challenges
Formal brain-training programs aren’t the only way to improve brain plasticity, Dr. Hara said. Observational studies suggested an association between improved cognitive performance and/or lower dementia risk and engaging in number and word puzzles, such as crosswords, cards, or board games.
Some studies suggested that older adults who use technology might also protect their cognitive reserve. Dr. Hara cited a US longitudinal study of more than 18,000 older adults suggesting that regular Internet users had roughly half the risk for dementia compared to nonregular Internet users. Estimates of daily Internet use suggested a U-shaped relationship with dementia with 0.1-2.0 hours daily (excluding time spent watching television or movies online) associated with the lowest risk. Similar associations between Internet use and a lower risk for cognitive decline have been reported in the United Kingdom and Europe.
“Engaging in mentally stimulating activities can increase ‘cognitive reserve’ — meaning, capacity of the brain to resist the effects of age-related changes or disease-related pathology, such that one can maintain cognitive function for longer,” Dr. Hara said. “Cognitively stimulating activities, regardless of the type, may help delay the onset of cognitive decline.”
She listed several examples of activities that are stimulating to the brain, including learning a new game or puzzle, a new language, or a new dance, and learning how to play a musical instrument.
Dr. Montero-Odasso emphasized that the “newness” is key to increasing and preserving cognitive reserve. “Just surfing the Internet, playing word or board games, or doing crossword puzzles won’t be enough if you’ve been doing these things all your life,” he said. “It won’t hurt, of course, but it won’t necessarily increase your cognitive abilities.
“For example, a person who regularly engages in public speaking may not improve cognition by taking a public-speaking course, but someone who has never spoken before an audience might show cognitive improvements as a result of learning a new skill,” he said. “Or someone who knows several languages already might gain from learning a brand-new language.”
He cited research supporting the benefits of dancing, which he called “an ideal activity because it’s physical, so it provides the exercise that’s been associated with improved cognition. But it also requires learning new steps and moves, which builds the synapses in the brain. And the socialization of dance classes adds another component that can improve cognition.”
Dr. Mahncke hopes that beyond engaging in day-to-day new activities, seniors will participate in computerized brain training. “There’s no reason that evidence-based training can’t be offered in senior and community centers, as yoga and swimming are,” he said. “It doesn’t have to be simply something people do on their own virtually.”
Zoom classes and Medicare reimbursements are “good steps in the right direction, but it’s time to expand this potentially life-transformative intervention so that it reaches the ever-expanding population of seniors in the United States and beyond.”
Dr. Hara reported having no disclosures. Dr. Montero-Odasso reported having no commercial or financial interest related to this topic. He serves as the president of the Canadian Geriatrics Société and is team leader in the Canadian Consortium of Neurodegeneration in Aging. Dr. Mahncke is CEO of the brain training company Posit Science/BrainHQ.
A version of this article appeared on Medscape.com.
Could Bedside Training Help End the US Neurologist Shortage?
DENVER — , a new report suggested.
Bedside Rounding Alliance for Internal Medicine and Neurology Residents (BRAINs) moves training from the lecture hall to the bedside, offering instruction on obtaining a focused neurologic history and performing a focused neurologic physical exam for common neurologic symptoms.
Almost 100% of trainees surveyed gave the program a favorable rating, citing patient exposure and bedside training from neurology educators as keys to its success.
As internal medicine providers are often “the first to lay eyes” on patients with a neurology complaint, it’s important they “have a basic level of comfort” in addressing patients’ common questions and concerns, study author Prashanth Rajarajan, MD, PhD, a resident in the Department of Neurology at Brigham and Women’s Hospital, Boston, told this news organization.
The findings were presented at the 2024 annual meeting of the American Academy of Neurology.
Addressing ‘Neurophobia’
Neurology is often viewed by medical trainees as the most difficult subspecialty, Dr. Rajarajan said. Many have what he calls “neurophobia,” which he defines as “a discomfort with assessing and treating neurologic complaints.”
A survey at his institution showed 62% of internal medicine residents lacked the confidence to diagnose and treat neurologic diseases, he reported.
BRAINs is a structured neurology trainee-led, inpatient bedside teaching session for internal medicine residents, medical students, and others that aims to increase trainees’ confidence in assessing patients with common neurologic symptoms.
The program includes a biweekly 45-minute session. Most of the session is spent at the bedside and involves demonstrations and practice of a focused neurologic history and physical exam.
Participants receive feedback from educators, typically neurology residents or fellows in epilepsy, stroke, or some other neurology subspecialty. It also includes a short discussion on pertinent diagnostics, management, and other topics.
Surveys evaluating the program and teaching skill development were completed by 59 residents and 15 neurology educators who participated in BRAINs between 2022 and 2024.
Over 90% of trainees (54) agreed BRAINs sessions met the program’s objective (5 were neutral); 49 agreed it increased confidence in taking a neuro history (9 were neutral and 1 disagreed); 56 felt it boosted their confidence in doing a neuro exam (3 were neutral); and 56 said BRAINs is more effective than traditional lecture-based didactics (3 were neutral).
All the residents rated the material covered as appropriate for their level of training; 88% considered the 45-minute session length appropriate; and 98% had a favorable impression of the program as a whole.
When asked to identify the most helpful aspect of the program, 82% cited more patient exposure and 81% more bedside teaching.
All educators reported that the sessions were an effective way to practice near-peer teaching skills. Most (87%) felt the experience was more effective at accomplishing learning objectives than preparing and giving traditional didactic lectures, and 80% agreed it also gave them an opportunity to get to know their medical colleagues.
Use It or Lose It
Dr. Rajarajan noted that the program doesn’t require significant planning or extra staff, is not resource-intensive, and can be adapted to different services such as emergency departments and other learner populations.
But time will tell if the newfound confidence of those taking the program actually lasts.
“You have to keep using it,” he said. “You use it or lose it when comes to these skills.”
Commenting on the initiative, Denney Zimmerman, DO, Neurocritical Care Faculty, Blount Memorial Hospital, Maryville, Tennessee, and cochair of the AAN session featuring the study, called the program a good example of one way to counteract “neurophobia” and address the widespread neurologist shortage in the United States.
A 2019 AAN report showed that by 2025, almost every state in the United States will have a mismatch between the number of practicing neurologists and the demand from patients with neurologic conditions. The report offered several ways to address the shortage, including more neurology-focused training for internal medicine doctors during their residency.
“They’re usually on the front line, both in the hospital and in the clinics, and can help expedite patients who need to be seen by neurology sooner rather than later,” Dr. Zimmerman said.
Dr. Zimmerman noted that the study assessed how well participants perceived the program but not whether it improved their skills.
He pointed out that different groups may assess different diseases during their training session. “I think it’s important to ensure you’re hitting all the major topics.”
The study received funding from MGB Centers of Expertise Education Grant. Drs. Rajarajan and Zimmerman reported no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
DENVER — , a new report suggested.
Bedside Rounding Alliance for Internal Medicine and Neurology Residents (BRAINs) moves training from the lecture hall to the bedside, offering instruction on obtaining a focused neurologic history and performing a focused neurologic physical exam for common neurologic symptoms.
Almost 100% of trainees surveyed gave the program a favorable rating, citing patient exposure and bedside training from neurology educators as keys to its success.
As internal medicine providers are often “the first to lay eyes” on patients with a neurology complaint, it’s important they “have a basic level of comfort” in addressing patients’ common questions and concerns, study author Prashanth Rajarajan, MD, PhD, a resident in the Department of Neurology at Brigham and Women’s Hospital, Boston, told this news organization.
The findings were presented at the 2024 annual meeting of the American Academy of Neurology.
Addressing ‘Neurophobia’
Neurology is often viewed by medical trainees as the most difficult subspecialty, Dr. Rajarajan said. Many have what he calls “neurophobia,” which he defines as “a discomfort with assessing and treating neurologic complaints.”
A survey at his institution showed 62% of internal medicine residents lacked the confidence to diagnose and treat neurologic diseases, he reported.
BRAINs is a structured neurology trainee-led, inpatient bedside teaching session for internal medicine residents, medical students, and others that aims to increase trainees’ confidence in assessing patients with common neurologic symptoms.
The program includes a biweekly 45-minute session. Most of the session is spent at the bedside and involves demonstrations and practice of a focused neurologic history and physical exam.
Participants receive feedback from educators, typically neurology residents or fellows in epilepsy, stroke, or some other neurology subspecialty. It also includes a short discussion on pertinent diagnostics, management, and other topics.
Surveys evaluating the program and teaching skill development were completed by 59 residents and 15 neurology educators who participated in BRAINs between 2022 and 2024.
Over 90% of trainees (54) agreed BRAINs sessions met the program’s objective (5 were neutral); 49 agreed it increased confidence in taking a neuro history (9 were neutral and 1 disagreed); 56 felt it boosted their confidence in doing a neuro exam (3 were neutral); and 56 said BRAINs is more effective than traditional lecture-based didactics (3 were neutral).
All the residents rated the material covered as appropriate for their level of training; 88% considered the 45-minute session length appropriate; and 98% had a favorable impression of the program as a whole.
When asked to identify the most helpful aspect of the program, 82% cited more patient exposure and 81% more bedside teaching.
All educators reported that the sessions were an effective way to practice near-peer teaching skills. Most (87%) felt the experience was more effective at accomplishing learning objectives than preparing and giving traditional didactic lectures, and 80% agreed it also gave them an opportunity to get to know their medical colleagues.
Use It or Lose It
Dr. Rajarajan noted that the program doesn’t require significant planning or extra staff, is not resource-intensive, and can be adapted to different services such as emergency departments and other learner populations.
But time will tell if the newfound confidence of those taking the program actually lasts.
“You have to keep using it,” he said. “You use it or lose it when comes to these skills.”
Commenting on the initiative, Denney Zimmerman, DO, Neurocritical Care Faculty, Blount Memorial Hospital, Maryville, Tennessee, and cochair of the AAN session featuring the study, called the program a good example of one way to counteract “neurophobia” and address the widespread neurologist shortage in the United States.
A 2019 AAN report showed that by 2025, almost every state in the United States will have a mismatch between the number of practicing neurologists and the demand from patients with neurologic conditions. The report offered several ways to address the shortage, including more neurology-focused training for internal medicine doctors during their residency.
“They’re usually on the front line, both in the hospital and in the clinics, and can help expedite patients who need to be seen by neurology sooner rather than later,” Dr. Zimmerman said.
Dr. Zimmerman noted that the study assessed how well participants perceived the program but not whether it improved their skills.
He pointed out that different groups may assess different diseases during their training session. “I think it’s important to ensure you’re hitting all the major topics.”
The study received funding from MGB Centers of Expertise Education Grant. Drs. Rajarajan and Zimmerman reported no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
DENVER — , a new report suggested.
Bedside Rounding Alliance for Internal Medicine and Neurology Residents (BRAINs) moves training from the lecture hall to the bedside, offering instruction on obtaining a focused neurologic history and performing a focused neurologic physical exam for common neurologic symptoms.
Almost 100% of trainees surveyed gave the program a favorable rating, citing patient exposure and bedside training from neurology educators as keys to its success.
As internal medicine providers are often “the first to lay eyes” on patients with a neurology complaint, it’s important they “have a basic level of comfort” in addressing patients’ common questions and concerns, study author Prashanth Rajarajan, MD, PhD, a resident in the Department of Neurology at Brigham and Women’s Hospital, Boston, told this news organization.
The findings were presented at the 2024 annual meeting of the American Academy of Neurology.
Addressing ‘Neurophobia’
Neurology is often viewed by medical trainees as the most difficult subspecialty, Dr. Rajarajan said. Many have what he calls “neurophobia,” which he defines as “a discomfort with assessing and treating neurologic complaints.”
A survey at his institution showed 62% of internal medicine residents lacked the confidence to diagnose and treat neurologic diseases, he reported.
BRAINs is a structured neurology trainee-led, inpatient bedside teaching session for internal medicine residents, medical students, and others that aims to increase trainees’ confidence in assessing patients with common neurologic symptoms.
The program includes a biweekly 45-minute session. Most of the session is spent at the bedside and involves demonstrations and practice of a focused neurologic history and physical exam.
Participants receive feedback from educators, typically neurology residents or fellows in epilepsy, stroke, or some other neurology subspecialty. It also includes a short discussion on pertinent diagnostics, management, and other topics.
Surveys evaluating the program and teaching skill development were completed by 59 residents and 15 neurology educators who participated in BRAINs between 2022 and 2024.
Over 90% of trainees (54) agreed BRAINs sessions met the program’s objective (5 were neutral); 49 agreed it increased confidence in taking a neuro history (9 were neutral and 1 disagreed); 56 felt it boosted their confidence in doing a neuro exam (3 were neutral); and 56 said BRAINs is more effective than traditional lecture-based didactics (3 were neutral).
All the residents rated the material covered as appropriate for their level of training; 88% considered the 45-minute session length appropriate; and 98% had a favorable impression of the program as a whole.
When asked to identify the most helpful aspect of the program, 82% cited more patient exposure and 81% more bedside teaching.
All educators reported that the sessions were an effective way to practice near-peer teaching skills. Most (87%) felt the experience was more effective at accomplishing learning objectives than preparing and giving traditional didactic lectures, and 80% agreed it also gave them an opportunity to get to know their medical colleagues.
Use It or Lose It
Dr. Rajarajan noted that the program doesn’t require significant planning or extra staff, is not resource-intensive, and can be adapted to different services such as emergency departments and other learner populations.
But time will tell if the newfound confidence of those taking the program actually lasts.
“You have to keep using it,” he said. “You use it or lose it when comes to these skills.”
Commenting on the initiative, Denney Zimmerman, DO, Neurocritical Care Faculty, Blount Memorial Hospital, Maryville, Tennessee, and cochair of the AAN session featuring the study, called the program a good example of one way to counteract “neurophobia” and address the widespread neurologist shortage in the United States.
A 2019 AAN report showed that by 2025, almost every state in the United States will have a mismatch between the number of practicing neurologists and the demand from patients with neurologic conditions. The report offered several ways to address the shortage, including more neurology-focused training for internal medicine doctors during their residency.
“They’re usually on the front line, both in the hospital and in the clinics, and can help expedite patients who need to be seen by neurology sooner rather than later,” Dr. Zimmerman said.
Dr. Zimmerman noted that the study assessed how well participants perceived the program but not whether it improved their skills.
He pointed out that different groups may assess different diseases during their training session. “I think it’s important to ensure you’re hitting all the major topics.”
The study received funding from MGB Centers of Expertise Education Grant. Drs. Rajarajan and Zimmerman reported no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
FROM AAN 2024
Migraine Drug Reduces Rosacea Flushing, Erythema in Small Study
In. Skin-related quality-of-life (QOL) measures also improved, albeit modestly.
The study was published in JAMA Dermatology.
“The transient erythema of rosacea is one of the most challenging rosacea symptoms to treat,” Emmy Graber, MD, MBA, who was not involved with the study, said in an interview. “As flushing can adversely impact quality of life in our rosacea patients, it is important to find therapeutic options for our patients. This study is exciting, not only because the treatment was successful for a notable number of patients, but also because it involved a drug with a novel mode of action in rosacea.” Dr. Graber practices in Boston and is an affiliate clinical instructor at Northeastern University, Boston.
Guy F. Webster, MD, PhD, clinical professor of dermatology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, added, “The interesting thing about this study is that it gives us a new target to think about for therapy. But it’s a long way from saying we can use it tomorrow.” He was not involved with the study but was also asked to comment on the findings.
Spotlight on CGRP
Rosacea’s pathophysiology remains incompletely understood, wrote Nita K.F. Wienholtz, MD, PhD, Department of Dermatology, Bispebjerg and Frederiksberg Hospital, University of Copenhagen, Denmark, and coinvestigators. However, they added, mounting evidence suggests a possible role for CGRP. For example, a study published in JAMA Dermatology in 2015 revealed elevated CGRP levels in facial skin biopsies from patients with rosacea.
For the present study, the investigators enrolled 30 adults (including 23 women) with rosacea who experienced at least 15 days of moderate to severe erythema or extreme flushing during a 4-week, treatment-free run-in period. Most participants (87%) had previously failed one or more rosacea treatments because of a lack of efficacy or adverse reactions, and 43% had failed three or more treatments.
Participants received 3-monthly 140-mg doses of erenumab, which is approved by the Food and Drug Administration for migraine prevention. Patients recorded scores on the Patient Self-Assessment (PSA) and item 2 of the Flushing Assessment Tool online daily and made a final follow-up visit 12 weeks after the third dose.
Among the 27 patients who completed the study, the mean number of days with moderate to severe flushing from week 9 to week 12 fell by 6.9 from 23.6 days over 4 weeks at baseline (P < .001). Patients most severely affected by flushing at baseline experienced an 81% decline in days with severe to extreme flushing. Overall, 26% of patients experienced at least 50% reductions in moderate to extreme flushing days. The number of days with moderate to severe erythema as measured by PSA fell by 8.1 (mean) from baseline, and 56% of patients experienced at least 50% reductions in PSA scores. No unexpected safety signals emerged.
Questions Over QOL Data
“Although there were significant decreases in flushing and erythema,” wrote John S. Barbieri, MD, MBA, in an accompanying Editor’s Note, “the present study had relatively modest improvements in quality of life.” He is director of the Advanced Acne Therapeutics Clinic, Brigham and Women’s Hospital, Boston, and associate editor and evidence-based practice editor of JAMA Dermatology.
Compared with baseline (6.22), mean Dermatology Life Quality Index scores fell 2.08 points and 2.73 points at weeks 8 and 20, respectively (P = .004 and .003). At the same intervals, the mean baseline Rosacea Quality of Life score (48.22) decreased by 2.58 points and 4.14 points, respectively (P = .04 and .02).
No significant changes appeared in gauges of anxiety and depression. These findings, authors wrote, could stem from their decision to omit a follow-up visit at week 12 — where they may have seen mental-health effects which disappeared by week 20 — in response to patients’ logistical concerns.
However, Dr. Webster questioned the value of QOL measurements in rosacea. “Quality-of-life measures are blunt instruments,” he explained, and reducing severe itching or chronic pain improves the lives of affected patients. “But what question are you going to ask to tease out whether being less red-cheeked has made someone’s life easier? It’s not a problem that lends itself to quality-of-life assessments.” Moreover, he said, regulators who increasingly require such measures in clinical trials ignore this point, creating challenges for drug developers and researchers.
Because the study was neither blinded nor controlled, Dr. Webster suggested considering it a tantalizing proof of concept. “If I were putting money into a CGRP inhibitor, I’d want at least a small, placebo-controlled, double-blinded study.”
Study authors and Dr. Barbieri recommended larger randomized studies involving different populations and erenumab doses. For now, Dr. Barbieri wrote, CGRP inhibition represents a promising potential strategy for patients who have rosacea with comorbid migraine or recalcitrant flushing and erythema.
Dr. Wienholtz reported no relevant financial interests. Dr. Barbieri had no related disclosures. Dr. Webster reported no relevant financial interests. Dr. Graber reported no conflicts related to erenumab but consults for other companies with rosacea-related products including Galderma. The study was supported by and conducted in collaboration with Novartis Pharma AG. Additional funding came from the Novo Nordisk Foundation and the Lundbeck Foundation.
A version of this article appeared on Medscape.com.
In. Skin-related quality-of-life (QOL) measures also improved, albeit modestly.
The study was published in JAMA Dermatology.
“The transient erythema of rosacea is one of the most challenging rosacea symptoms to treat,” Emmy Graber, MD, MBA, who was not involved with the study, said in an interview. “As flushing can adversely impact quality of life in our rosacea patients, it is important to find therapeutic options for our patients. This study is exciting, not only because the treatment was successful for a notable number of patients, but also because it involved a drug with a novel mode of action in rosacea.” Dr. Graber practices in Boston and is an affiliate clinical instructor at Northeastern University, Boston.
Guy F. Webster, MD, PhD, clinical professor of dermatology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, added, “The interesting thing about this study is that it gives us a new target to think about for therapy. But it’s a long way from saying we can use it tomorrow.” He was not involved with the study but was also asked to comment on the findings.
Spotlight on CGRP
Rosacea’s pathophysiology remains incompletely understood, wrote Nita K.F. Wienholtz, MD, PhD, Department of Dermatology, Bispebjerg and Frederiksberg Hospital, University of Copenhagen, Denmark, and coinvestigators. However, they added, mounting evidence suggests a possible role for CGRP. For example, a study published in JAMA Dermatology in 2015 revealed elevated CGRP levels in facial skin biopsies from patients with rosacea.
For the present study, the investigators enrolled 30 adults (including 23 women) with rosacea who experienced at least 15 days of moderate to severe erythema or extreme flushing during a 4-week, treatment-free run-in period. Most participants (87%) had previously failed one or more rosacea treatments because of a lack of efficacy or adverse reactions, and 43% had failed three or more treatments.
Participants received 3-monthly 140-mg doses of erenumab, which is approved by the Food and Drug Administration for migraine prevention. Patients recorded scores on the Patient Self-Assessment (PSA) and item 2 of the Flushing Assessment Tool online daily and made a final follow-up visit 12 weeks after the third dose.
Among the 27 patients who completed the study, the mean number of days with moderate to severe flushing from week 9 to week 12 fell by 6.9 from 23.6 days over 4 weeks at baseline (P < .001). Patients most severely affected by flushing at baseline experienced an 81% decline in days with severe to extreme flushing. Overall, 26% of patients experienced at least 50% reductions in moderate to extreme flushing days. The number of days with moderate to severe erythema as measured by PSA fell by 8.1 (mean) from baseline, and 56% of patients experienced at least 50% reductions in PSA scores. No unexpected safety signals emerged.
Questions Over QOL Data
“Although there were significant decreases in flushing and erythema,” wrote John S. Barbieri, MD, MBA, in an accompanying Editor’s Note, “the present study had relatively modest improvements in quality of life.” He is director of the Advanced Acne Therapeutics Clinic, Brigham and Women’s Hospital, Boston, and associate editor and evidence-based practice editor of JAMA Dermatology.
Compared with baseline (6.22), mean Dermatology Life Quality Index scores fell 2.08 points and 2.73 points at weeks 8 and 20, respectively (P = .004 and .003). At the same intervals, the mean baseline Rosacea Quality of Life score (48.22) decreased by 2.58 points and 4.14 points, respectively (P = .04 and .02).
No significant changes appeared in gauges of anxiety and depression. These findings, authors wrote, could stem from their decision to omit a follow-up visit at week 12 — where they may have seen mental-health effects which disappeared by week 20 — in response to patients’ logistical concerns.
However, Dr. Webster questioned the value of QOL measurements in rosacea. “Quality-of-life measures are blunt instruments,” he explained, and reducing severe itching or chronic pain improves the lives of affected patients. “But what question are you going to ask to tease out whether being less red-cheeked has made someone’s life easier? It’s not a problem that lends itself to quality-of-life assessments.” Moreover, he said, regulators who increasingly require such measures in clinical trials ignore this point, creating challenges for drug developers and researchers.
Because the study was neither blinded nor controlled, Dr. Webster suggested considering it a tantalizing proof of concept. “If I were putting money into a CGRP inhibitor, I’d want at least a small, placebo-controlled, double-blinded study.”
Study authors and Dr. Barbieri recommended larger randomized studies involving different populations and erenumab doses. For now, Dr. Barbieri wrote, CGRP inhibition represents a promising potential strategy for patients who have rosacea with comorbid migraine or recalcitrant flushing and erythema.
Dr. Wienholtz reported no relevant financial interests. Dr. Barbieri had no related disclosures. Dr. Webster reported no relevant financial interests. Dr. Graber reported no conflicts related to erenumab but consults for other companies with rosacea-related products including Galderma. The study was supported by and conducted in collaboration with Novartis Pharma AG. Additional funding came from the Novo Nordisk Foundation and the Lundbeck Foundation.
A version of this article appeared on Medscape.com.
In. Skin-related quality-of-life (QOL) measures also improved, albeit modestly.
The study was published in JAMA Dermatology.
“The transient erythema of rosacea is one of the most challenging rosacea symptoms to treat,” Emmy Graber, MD, MBA, who was not involved with the study, said in an interview. “As flushing can adversely impact quality of life in our rosacea patients, it is important to find therapeutic options for our patients. This study is exciting, not only because the treatment was successful for a notable number of patients, but also because it involved a drug with a novel mode of action in rosacea.” Dr. Graber practices in Boston and is an affiliate clinical instructor at Northeastern University, Boston.
Guy F. Webster, MD, PhD, clinical professor of dermatology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, added, “The interesting thing about this study is that it gives us a new target to think about for therapy. But it’s a long way from saying we can use it tomorrow.” He was not involved with the study but was also asked to comment on the findings.
Spotlight on CGRP
Rosacea’s pathophysiology remains incompletely understood, wrote Nita K.F. Wienholtz, MD, PhD, Department of Dermatology, Bispebjerg and Frederiksberg Hospital, University of Copenhagen, Denmark, and coinvestigators. However, they added, mounting evidence suggests a possible role for CGRP. For example, a study published in JAMA Dermatology in 2015 revealed elevated CGRP levels in facial skin biopsies from patients with rosacea.
For the present study, the investigators enrolled 30 adults (including 23 women) with rosacea who experienced at least 15 days of moderate to severe erythema or extreme flushing during a 4-week, treatment-free run-in period. Most participants (87%) had previously failed one or more rosacea treatments because of a lack of efficacy or adverse reactions, and 43% had failed three or more treatments.
Participants received 3-monthly 140-mg doses of erenumab, which is approved by the Food and Drug Administration for migraine prevention. Patients recorded scores on the Patient Self-Assessment (PSA) and item 2 of the Flushing Assessment Tool online daily and made a final follow-up visit 12 weeks after the third dose.
Among the 27 patients who completed the study, the mean number of days with moderate to severe flushing from week 9 to week 12 fell by 6.9 from 23.6 days over 4 weeks at baseline (P < .001). Patients most severely affected by flushing at baseline experienced an 81% decline in days with severe to extreme flushing. Overall, 26% of patients experienced at least 50% reductions in moderate to extreme flushing days. The number of days with moderate to severe erythema as measured by PSA fell by 8.1 (mean) from baseline, and 56% of patients experienced at least 50% reductions in PSA scores. No unexpected safety signals emerged.
Questions Over QOL Data
“Although there were significant decreases in flushing and erythema,” wrote John S. Barbieri, MD, MBA, in an accompanying Editor’s Note, “the present study had relatively modest improvements in quality of life.” He is director of the Advanced Acne Therapeutics Clinic, Brigham and Women’s Hospital, Boston, and associate editor and evidence-based practice editor of JAMA Dermatology.
Compared with baseline (6.22), mean Dermatology Life Quality Index scores fell 2.08 points and 2.73 points at weeks 8 and 20, respectively (P = .004 and .003). At the same intervals, the mean baseline Rosacea Quality of Life score (48.22) decreased by 2.58 points and 4.14 points, respectively (P = .04 and .02).
No significant changes appeared in gauges of anxiety and depression. These findings, authors wrote, could stem from their decision to omit a follow-up visit at week 12 — where they may have seen mental-health effects which disappeared by week 20 — in response to patients’ logistical concerns.
However, Dr. Webster questioned the value of QOL measurements in rosacea. “Quality-of-life measures are blunt instruments,” he explained, and reducing severe itching or chronic pain improves the lives of affected patients. “But what question are you going to ask to tease out whether being less red-cheeked has made someone’s life easier? It’s not a problem that lends itself to quality-of-life assessments.” Moreover, he said, regulators who increasingly require such measures in clinical trials ignore this point, creating challenges for drug developers and researchers.
Because the study was neither blinded nor controlled, Dr. Webster suggested considering it a tantalizing proof of concept. “If I were putting money into a CGRP inhibitor, I’d want at least a small, placebo-controlled, double-blinded study.”
Study authors and Dr. Barbieri recommended larger randomized studies involving different populations and erenumab doses. For now, Dr. Barbieri wrote, CGRP inhibition represents a promising potential strategy for patients who have rosacea with comorbid migraine or recalcitrant flushing and erythema.
Dr. Wienholtz reported no relevant financial interests. Dr. Barbieri had no related disclosures. Dr. Webster reported no relevant financial interests. Dr. Graber reported no conflicts related to erenumab but consults for other companies with rosacea-related products including Galderma. The study was supported by and conducted in collaboration with Novartis Pharma AG. Additional funding came from the Novo Nordisk Foundation and the Lundbeck Foundation.
A version of this article appeared on Medscape.com.
FROM JAMA DERMATOLOGY
