Neurology

Calcitonin gene-related peptide (CGRP) is a neuropeptide that plays a key role in migraine pathophysiology by promoting the dilation of cerebral blood vessels and transmitting pain signals.¹ CGRP has generated interest for the prevention and acute treatment of migraine. Since 2018, 8 novel CGRP-targeting therapies have been approved by the US Food and Drug Administration (FDA) for the management of migraines.^2,3 For migraine prevention, there are 4 injectable monoclonal antibodies (mAbs) directed against the CGRP receptor (erenumab) or the CGRP ligand (fremanezumab, galcanezumab, and eptinezumab). There are also 2 oral small-molecule CGRP receptor antagonists, termed gepants, that also are approved for migraine prevention (atogepant and rimegepant). Three gepants are approved for acute migraine treatment and are administered orally (rimegepant and ubrogepant) or intranasally (zavegepant) (Table 1).

CGRP-targeting therapies have received attention for their role in vasodilation within the cerebral, coronary, and renal vasculature.⁴ CGRP-mediated vasodilatory effects cause systemic regulation of blood pressure (BP) and play a protective role in hypertension.² Some studies, particularly with erenumab, have shown that the inhibitory role of the agent leads to an increase in BP, as well as gastrointestinal issues such as constipation.^2,5 The FDA recently updated monitoring recommendations for all CGRP-targeting therapies to include the potential for BP elevations and hypertension. Outside of this, there is no definitive evidence linking dual CGRP-targeted therapy to higher cardiovascular or gastrointestinal risks and prescribing information does not carry contraindications.⁶

In a 2021 consensus statement, the American Headache Society (AHS) recommended CGRP-targeting therapies for migraine prevention after inability to tolerate or inadequate response to an 8-week trial of ≥ 2 drug classes including antihypertensives, antiseizure medications, antidepressants, and onabotulinumtoxinA.⁷ For acute treatment, AHS recommended gepant use after contraindication to or inadequate response to ≥ 2 triptans. Guidance on combination CGRP-targeting therapies for both prevention and acute treatment was not provided.⁷ More recently, the AHS published a position statement noting substantial efficacy and safety data for CGRP-targeting therapies and suggested its consideration as a first-line option for migraine prevention, though use for acute treatment or combination CGRP-targeting therapies for both prevention and acute treatment were not addressed.⁸

The International Headache Society guidelines for the acute treatment of migraines recommend nonopioid analgesics as first-line therapy for mild migraine attacks. For moderate to severe attacks, triptans with or without a nonopioid analgesic were recommended as first-line therapy, prior to consideration of CGRP-targeted therapy.⁹ The increased use of this new drug class has also led to combination use of CGRP-targeting therapies for migraine prevention and acute treatment as seen in clinical practice and reflected by some case reports, case series, and small studies describing such use.^10-14 In light of the similar mechanism of action of these therapies and the physiologic role of CGRP, there have been calls for safety evaluation.¹⁵

To our knowledge, no studies have evaluated dual CGRP-targeting regimens for migraine in the veteran population. In 2023, the US Department of Veterans Affairs (VA) and US Department of Defense (DoD) updated their clinical practice guidelines for the management of headache.³ For migraine prevention, the VA/DoD guidelines include a strong recommendation for the use of erenumab, fremanezumab, and galcanezumab; a weak recommendation for the use of atogepant; and a recommendation neither for nor against the use of rimegepant. For acute treatment, the guidelines assign a weak recommendation for the use of rimegepant and ubrogepant. Combination use was not addressed.³

Prior to the VA/DoD guidelines, the Veterans Health Administration restricted the dual use of CGRP-targeting therapies for both preventive and acute migraine treatment. However, the VA Pharmacy Benefit Management Service removed the restriction in the Criteria for Use documents, allowing broader access to these medications for veterans.^16-22 This change permits the use of CGRP-targeting drugs for both acute and preventive migraine treatment after initial data reflecting real-world case reports and open-label studies suggested possible efficacy without a clear safety concern.^11,12 This study aims to fill the gap in the literature by evaluating the safety, efficacy, and overall outcomes of combination CGRP-targeting treatment for migraine prevention and acute treatment in a veteran population.

Methods

This single-center, retrospective, medication use evaluation at the Ralph H. Johnson VA Medical Center (RHJVAMC) was reviewed by the RHJVAMC Research and Development Committee and Quality Improvement Program Evaluation Self Certification Tool, which both determined that institutional review board approval was not required because it was considered part of routine care and quality improvement. Computerized Patient Record System (CPRS) data were reviewed between April 1, 2023 (after the Criteria for Use for CGRP-targeting therapies was updated), through January 31, 2025. Patients were included if they had a confirmed diagnosis of migraine using the International Classification of Headache Disorders, 3rd edition criteria and had concomitant active prescriptions for both a preventive and acute treatment CGRP-targeting agent during the project period.²³ Only patients receiving care from the RHJVAMC neurology department were included.

The primary objective was to assess the safety of dual CGRP-targeting therapies for migraine treatment. Key safety endpoints included effects on liver function, kidney function, and BP. Safety outcomes were graded using Common Terminology Criteria for Adverse Events.²⁴ Changes in liver function were categorized as grade 1, 2, or 3 elevations: grade 1 (aspartate aminotransferase [AST]/alanine aminotransferase [ALT] up to 3x the upper limit of normal [ULN] or bilirubin > 1.5 x ULN); grade 2 (AST/ALT 3-6 x ULN or bilirubin 1.5-3 x ULN); and grade 3 (AST/ALT 5-10 x ULN or bilirubin 3-10 x ULN). Kidney function changes were assessed by serum creatinine levels using a similar grading system: Grade 1 (≤ 1.5 x ULN); grade 2 (1.5-3 x baseline of normal); and grade 3 (3-6 x ULN or baseline). Changes in BP were monitored from baseline to the time of the first neurology follow-up. Elevations were grouped into 2 categories, defined as BP ≥ 140 mm Hg systolic and/or 90 mm Hg diastolic (category 1) and ≥ 160 mm Hg systolic and/or 100 mm Hg diastolic (category 2). Neurology documentation was also reviewed in CPRS for individual patient-reported adverse effects (AEs). Safety endpoints were tracked for any occurrence during the project period.

The secondary objective was to describe the patient-reported efficacy of adding a gepant for acute migraine treatment to existing CGRP-targeting therapies for migraine prevention, in those patients who were stable for ≥ 12 weeks on the preventive therapy. Neurology documentation of headache characteristics, including headache severity as rated on a numerical pain score from 0 (no pain) to 10 (worst pain), and duration of headaches (in hours) were recorded during the project period. Changes in headache characteristics were tracked from baseline (ie, the neurology visit when the gepant was first requested) to the first neurology follow-up within 6 months of initiating gepant for acute treatment. If ranges were provided within documentation, a mean was calculated and used for data collection. Neurology documentation was also reviewed for any patient report of overall effectiveness with the added gepant, and categorized as symptoms improved, worsened, or did not change based on subjective report. Descriptive statistics were used for data analysis. A 1-sample Wilcoxon signed rank test was performed as an exploratory analysis for change in headache characteristics from baseline to first neurology follow-up within 6 months. Each individual CGRP regimen was counted as a unique data point to adequately describe changes associated with each new medication and/or dose adjustment. Therefore, patients could be included more than once to account for each distinct treatment regimen.

Results

From April 1, 2023, to January 31, 2025, 96 patients were identified with active prescriptions for dual CGRP-targeting therapies. Of the 96 patients, 89 were included in the final analysis; 1 patient lacked a migraine diagnosis and 6 did not have a concomitant dual CGRP-targeted regimen and were excluded. The mean age of patients was 46.8 years and 54 (61%) were female. The most common migraine diagnosis was chronic migraine in 68 patients (76%). Triptans, ibuprofen, and acetaminophen were the most commonly used acute treatment medications (Table 2).

Safety Assessment

Many of the 89 unique patients trialed > 1 regimen. Thus, for the safety analysis, we analyzed 149 patients on unique dual CGRP-targeting regimens (Table 3). Ubrogepant was used by 126 patients (84.6%) for acute treatment. For preventive therapy, 63 patients (42.3%) used erenumab injections and 55 (36.9%) used fremanezumab injections. Seven patients (4.7%) reported AEs (Table 4). Five of the 7 AEs were noted in the package inserts.^25-32 One patient taking both atogepant and ubrogepant reported brain fog that resolved after a dose reduction of atogepant to every other day dosing. A patient taking fremanezumab and rimegepant reported myalgia/joint pain after the first fremanezumab injection, which resolved after a few days and did not recur during the study period.

Nine of 149 patient regimens (6.0%) were associated with changes in liver function tests or serum creatinine, though all but 1 were grade 1 (1 patient had a grade 2 ALT elevation). Twenty-five patients (16.8%) experienced changes in BP, most of which were category 1 elevations. Four patients had systolic or diastolic BP ≥ 160 mm Hg or 100 mm Hg, respectively (Table 5).

Efficacy Assessment

Of the 149 unique dual CGRP regimens, 59 were eligible for the exploratory efficacy analysis. Data were excluded from the efficacy analysis if patients had not been on a stable CGRP preventive migraine regimen for ≥ 12 weeks prior to the addition of a gepant. Fourteen regimens were excluded due to a lack of clear documentation on efficacy, leaving 45 analyzed regimens. Of the 45 regimens, 34 were from unique patients. There was no median change in migraine intensity or duration found in the efficacy analysis (0.0, P = .18, and 0.0, P = .92, respectively). Ten patients on dual CGRP therapy reported that the addition of a gepant for acute treatment improved their symptoms, 20 reported that their symptoms were unchanged and/or worsened, and 29 lacked documentation.

Discussion

This study aimed to describe the safety and efficacy of concomitant CGRP regimens for migraine prevention and acute treatment. To our knowledge, this was the first descriptive study of these agents in a veteran population. The potential for increased AEs with concomitant use of CGRP antagonists is due to the similarities in the mechanism of action between the agents, which both target the same receptor/ligand pathway. Given CGRP activity in both the gastrointestinal and cardiovascular systems, the potential for related AEs is speculative. Patient-reported AEs occurred in 7 of 149 unique treatment regimens reviewed for an incidence rate < 5%. All AEs were nonserious and self-limiting.

Our findings are consistent with available research. A 2024 retrospective, exploratory real-world study evaluating the safety and tolerability of combining CGRP-targeting mAbs with gepants reported findings consistent with our results. This analysis included adult patients treated with ≥ 1 previous anti-CGRP mAb and found that 234 of 516 patients included received a combination of a gepant in addition to a CGRP-targeting mAb. Of these 234 patients, 1.3% reported nonserious AEs.³³ Similarly, in a multicenter, open-label, long-term safety study in adults experiencing multiple monthly migraine attacks, a subgroup of 13 participants taking a stable dose of an anti-CGRP mAb also took rimegepant 75 mg as needed for acute treatment for 12 weeks. These patients experienced no serious AEs or any AEs leading to discontinuation.¹⁴ A study evaluating the drug-drug interaction, safety, and tolerability of dual therapy (atogepant 60 mg daily and ubrogepant 100 mg every 3 days) in 26 patients found no serious AEs, including no significant changes from baseline in laboratory results, vital signs, or safety-related 12-lead electrocardiogram parameters.¹⁵The TANDEM real-world, open-label, prospective study demonstrated similar results. It evaluated the safety and tolerability of concomitant use of ubrogepant and atogepant in patients with episodic migraines and found no increase in AEs when comparing atogepant alone with combination therapy. Twenty-six patients (9.9%) discontinued treatment due to AEs. The most common treatment-related AEs were constipation, nausea, decreased appetite, and fatigue. Efficacy data were also noted to be an exploratory endpoint in the TANDEM study; however, results have not been published.¹²

Within this safety analysis, new onset gastrointestinal AEs, specifically nausea, only occurred in 1 patient. Hypertension occurred in 25 treatment regimens (16.8%) for 21 unique patients (4 BP elevations occurred in 1 patient on 4 different regimens). However, the retrospective nature of reporting may limit accurate assessment. A closer analysis determined that elevated BP readings correlated with elevated pain scores at the time of the readings, which could have factored into the BP elevations. However, ongoing monitoring is needed due to an increased risk of hypertension, particularly given recent FDA labeling updates for CGRP-targeting therapies including gepants. In light of this, and the overall low incidence of hypertension reported, no new safety concerns were identified.

Limitations

Efficacy data in this project were exploratory. This evaluation did not show a significant difference in migraine intensity or duration after adding a gepant for acute treatment. The study was not powered to detect a significant difference. Limited data exist assessing efficacy outcomes with dual CGRP-targeting treatment regimens. The COURAGE study assessed the real-world effectiveness of ubrogepant and CGRP mAbs with or without the addition of onabotulinumtoxinA. The final analysis of the ubrogepant and CGRP mAb arm included 245 total patients and assessed meaningful migraine pain relief, restoration of normal function after a migraine, and treatment satisfaction. By hour 2, 61.6% of patients reported achieving migraine pain relief, rising to 80.4% by hour 4. Return to normal function occurred in 34.7% at hour 2 and 55.5% by hour 4.¹³ The long-term safety and efficacy of combining erenumab and rimegepant were described in a case series involving 2 patients. Both patients reported that the concomitant CGRP-targeted therapies were effective and reported no AEs.¹⁴

The retrospective design of this study meant that there was potential for limited documentation and introduction of bias into the results. Data were collected at a single VA health care system, and thus, results may not be generalizable to a broader population. However, the study population was consistent with the higher incidence of migraine expected in females in the general population. The sample size was limited, particularly in the exploratory efficacy endpoint assessment.

Limitations were observed due to inconsistent documentation regarding headache characteristics, making it challenging to draw meaningful conclusions from this data set. Additional confounding factors, including polypharmacy, nonadherence to medications, and comorbidities, may have skewed results. For example, while our study design required that the preventive CGRP-targeting medication be stable for 12 weeks for inclusion in further efficacy analysis, other medications commonly used for migraine prevention may have been adjusted (which was not accounted for in this analysis). Given this, more large-scale, placebo-controlled, randomized studies are needed to continue to assess the safety and efficacy of these combination treatment regimens.

Conclusions

Few AEs or safety events were reported with combination CGRP-targeting treatment for acute and preventive treatment of migraine. Those that were identified were considered mild. Efficacy data were limited, and further studies are needed to fully assess outcomes.

Calcitonin gene-related peptide (CGRP) is a neuropeptide that plays a key role in migraine pathophysiology by promoting the dilation of cerebral blood vessels and transmitting pain signals.¹ CGRP has generated interest for the prevention and acute treatment of migraine. Since 2018, 8 novel CGRP-targeting therapies have been approved by the US Food and Drug Administration (FDA) for the management of migraines.^2,3 For migraine prevention, there are 4 injectable monoclonal antibodies (mAbs) directed against the CGRP receptor (erenumab) or the CGRP ligand (fremanezumab, galcanezumab, and eptinezumab). There are also 2 oral small-molecule CGRP receptor antagonists, termed gepants, that also are approved for migraine prevention (atogepant and rimegepant). Three gepants are approved for acute migraine treatment and are administered orally (rimegepant and ubrogepant) or intranasally (zavegepant) (Table 1).

CGRP-targeting therapies have received attention for their role in vasodilation within the cerebral, coronary, and renal vasculature.⁴ CGRP-mediated vasodilatory effects cause systemic regulation of blood pressure (BP) and play a protective role in hypertension.² Some studies, particularly with erenumab, have shown that the inhibitory role of the agent leads to an increase in BP, as well as gastrointestinal issues such as constipation.^2,5 The FDA recently updated monitoring recommendations for all CGRP-targeting therapies to include the potential for BP elevations and hypertension. Outside of this, there is no definitive evidence linking dual CGRP-targeted therapy to higher cardiovascular or gastrointestinal risks and prescribing information does not carry contraindications.⁶

In a 2021 consensus statement, the American Headache Society (AHS) recommended CGRP-targeting therapies for migraine prevention after inability to tolerate or inadequate response to an 8-week trial of ≥ 2 drug classes including antihypertensives, antiseizure medications, antidepressants, and onabotulinumtoxinA.⁷ For acute treatment, AHS recommended gepant use after contraindication to or inadequate response to ≥ 2 triptans. Guidance on combination CGRP-targeting therapies for both prevention and acute treatment was not provided.⁷ More recently, the AHS published a position statement noting substantial efficacy and safety data for CGRP-targeting therapies and suggested its consideration as a first-line option for migraine prevention, though use for acute treatment or combination CGRP-targeting therapies for both prevention and acute treatment were not addressed.⁸

The International Headache Society guidelines for the acute treatment of migraines recommend nonopioid analgesics as first-line therapy for mild migraine attacks. For moderate to severe attacks, triptans with or without a nonopioid analgesic were recommended as first-line therapy, prior to consideration of CGRP-targeted therapy.⁹ The increased use of this new drug class has also led to combination use of CGRP-targeting therapies for migraine prevention and acute treatment as seen in clinical practice and reflected by some case reports, case series, and small studies describing such use.^10-14 In light of the similar mechanism of action of these therapies and the physiologic role of CGRP, there have been calls for safety evaluation.¹⁵

To our knowledge, no studies have evaluated dual CGRP-targeting regimens for migraine in the veteran population. In 2023, the US Department of Veterans Affairs (VA) and US Department of Defense (DoD) updated their clinical practice guidelines for the management of headache.³ For migraine prevention, the VA/DoD guidelines include a strong recommendation for the use of erenumab, fremanezumab, and galcanezumab; a weak recommendation for the use of atogepant; and a recommendation neither for nor against the use of rimegepant. For acute treatment, the guidelines assign a weak recommendation for the use of rimegepant and ubrogepant. Combination use was not addressed.³

Prior to the VA/DoD guidelines, the Veterans Health Administration restricted the dual use of CGRP-targeting therapies for both preventive and acute migraine treatment. However, the VA Pharmacy Benefit Management Service removed the restriction in the Criteria for Use documents, allowing broader access to these medications for veterans.^16-22 This change permits the use of CGRP-targeting drugs for both acute and preventive migraine treatment after initial data reflecting real-world case reports and open-label studies suggested possible efficacy without a clear safety concern.^11,12 This study aims to fill the gap in the literature by evaluating the safety, efficacy, and overall outcomes of combination CGRP-targeting treatment for migraine prevention and acute treatment in a veteran population.

Methods

This single-center, retrospective, medication use evaluation at the Ralph H. Johnson VA Medical Center (RHJVAMC) was reviewed by the RHJVAMC Research and Development Committee and Quality Improvement Program Evaluation Self Certification Tool, which both determined that institutional review board approval was not required because it was considered part of routine care and quality improvement. Computerized Patient Record System (CPRS) data were reviewed between April 1, 2023 (after the Criteria for Use for CGRP-targeting therapies was updated), through January 31, 2025. Patients were included if they had a confirmed diagnosis of migraine using the International Classification of Headache Disorders, 3rd edition criteria and had concomitant active prescriptions for both a preventive and acute treatment CGRP-targeting agent during the project period.²³ Only patients receiving care from the RHJVAMC neurology department were included.

The primary objective was to assess the safety of dual CGRP-targeting therapies for migraine treatment. Key safety endpoints included effects on liver function, kidney function, and BP. Safety outcomes were graded using Common Terminology Criteria for Adverse Events.²⁴ Changes in liver function were categorized as grade 1, 2, or 3 elevations: grade 1 (aspartate aminotransferase [AST]/alanine aminotransferase [ALT] up to 3x the upper limit of normal [ULN] or bilirubin > 1.5 x ULN); grade 2 (AST/ALT 3-6 x ULN or bilirubin 1.5-3 x ULN); and grade 3 (AST/ALT 5-10 x ULN or bilirubin 3-10 x ULN). Kidney function changes were assessed by serum creatinine levels using a similar grading system: Grade 1 (≤ 1.5 x ULN); grade 2 (1.5-3 x baseline of normal); and grade 3 (3-6 x ULN or baseline). Changes in BP were monitored from baseline to the time of the first neurology follow-up. Elevations were grouped into 2 categories, defined as BP ≥ 140 mm Hg systolic and/or 90 mm Hg diastolic (category 1) and ≥ 160 mm Hg systolic and/or 100 mm Hg diastolic (category 2). Neurology documentation was also reviewed in CPRS for individual patient-reported adverse effects (AEs). Safety endpoints were tracked for any occurrence during the project period.

The secondary objective was to describe the patient-reported efficacy of adding a gepant for acute migraine treatment to existing CGRP-targeting therapies for migraine prevention, in those patients who were stable for ≥ 12 weeks on the preventive therapy. Neurology documentation of headache characteristics, including headache severity as rated on a numerical pain score from 0 (no pain) to 10 (worst pain), and duration of headaches (in hours) were recorded during the project period. Changes in headache characteristics were tracked from baseline (ie, the neurology visit when the gepant was first requested) to the first neurology follow-up within 6 months of initiating gepant for acute treatment. If ranges were provided within documentation, a mean was calculated and used for data collection. Neurology documentation was also reviewed for any patient report of overall effectiveness with the added gepant, and categorized as symptoms improved, worsened, or did not change based on subjective report. Descriptive statistics were used for data analysis. A 1-sample Wilcoxon signed rank test was performed as an exploratory analysis for change in headache characteristics from baseline to first neurology follow-up within 6 months. Each individual CGRP regimen was counted as a unique data point to adequately describe changes associated with each new medication and/or dose adjustment. Therefore, patients could be included more than once to account for each distinct treatment regimen.

Results

From April 1, 2023, to January 31, 2025, 96 patients were identified with active prescriptions for dual CGRP-targeting therapies. Of the 96 patients, 89 were included in the final analysis; 1 patient lacked a migraine diagnosis and 6 did not have a concomitant dual CGRP-targeted regimen and were excluded. The mean age of patients was 46.8 years and 54 (61%) were female. The most common migraine diagnosis was chronic migraine in 68 patients (76%). Triptans, ibuprofen, and acetaminophen were the most commonly used acute treatment medications (Table 2).

Safety Assessment

Many of the 89 unique patients trialed > 1 regimen. Thus, for the safety analysis, we analyzed 149 patients on unique dual CGRP-targeting regimens (Table 3). Ubrogepant was used by 126 patients (84.6%) for acute treatment. For preventive therapy, 63 patients (42.3%) used erenumab injections and 55 (36.9%) used fremanezumab injections. Seven patients (4.7%) reported AEs (Table 4). Five of the 7 AEs were noted in the package inserts.^25-32 One patient taking both atogepant and ubrogepant reported brain fog that resolved after a dose reduction of atogepant to every other day dosing. A patient taking fremanezumab and rimegepant reported myalgia/joint pain after the first fremanezumab injection, which resolved after a few days and did not recur during the study period.

Nine of 149 patient regimens (6.0%) were associated with changes in liver function tests or serum creatinine, though all but 1 were grade 1 (1 patient had a grade 2 ALT elevation). Twenty-five patients (16.8%) experienced changes in BP, most of which were category 1 elevations. Four patients had systolic or diastolic BP ≥ 160 mm Hg or 100 mm Hg, respectively (Table 5).

Efficacy Assessment

Of the 149 unique dual CGRP regimens, 59 were eligible for the exploratory efficacy analysis. Data were excluded from the efficacy analysis if patients had not been on a stable CGRP preventive migraine regimen for ≥ 12 weeks prior to the addition of a gepant. Fourteen regimens were excluded due to a lack of clear documentation on efficacy, leaving 45 analyzed regimens. Of the 45 regimens, 34 were from unique patients. There was no median change in migraine intensity or duration found in the efficacy analysis (0.0, P = .18, and 0.0, P = .92, respectively). Ten patients on dual CGRP therapy reported that the addition of a gepant for acute treatment improved their symptoms, 20 reported that their symptoms were unchanged and/or worsened, and 29 lacked documentation.

Discussion

This study aimed to describe the safety and efficacy of concomitant CGRP regimens for migraine prevention and acute treatment. To our knowledge, this was the first descriptive study of these agents in a veteran population. The potential for increased AEs with concomitant use of CGRP antagonists is due to the similarities in the mechanism of action between the agents, which both target the same receptor/ligand pathway. Given CGRP activity in both the gastrointestinal and cardiovascular systems, the potential for related AEs is speculative. Patient-reported AEs occurred in 7 of 149 unique treatment regimens reviewed for an incidence rate < 5%. All AEs were nonserious and self-limiting.

Our findings are consistent with available research. A 2024 retrospective, exploratory real-world study evaluating the safety and tolerability of combining CGRP-targeting mAbs with gepants reported findings consistent with our results. This analysis included adult patients treated with ≥ 1 previous anti-CGRP mAb and found that 234 of 516 patients included received a combination of a gepant in addition to a CGRP-targeting mAb. Of these 234 patients, 1.3% reported nonserious AEs.³³ Similarly, in a multicenter, open-label, long-term safety study in adults experiencing multiple monthly migraine attacks, a subgroup of 13 participants taking a stable dose of an anti-CGRP mAb also took rimegepant 75 mg as needed for acute treatment for 12 weeks. These patients experienced no serious AEs or any AEs leading to discontinuation.¹⁴ A study evaluating the drug-drug interaction, safety, and tolerability of dual therapy (atogepant 60 mg daily and ubrogepant 100 mg every 3 days) in 26 patients found no serious AEs, including no significant changes from baseline in laboratory results, vital signs, or safety-related 12-lead electrocardiogram parameters.¹⁵The TANDEM real-world, open-label, prospective study demonstrated similar results. It evaluated the safety and tolerability of concomitant use of ubrogepant and atogepant in patients with episodic migraines and found no increase in AEs when comparing atogepant alone with combination therapy. Twenty-six patients (9.9%) discontinued treatment due to AEs. The most common treatment-related AEs were constipation, nausea, decreased appetite, and fatigue. Efficacy data were also noted to be an exploratory endpoint in the TANDEM study; however, results have not been published.¹²

Within this safety analysis, new onset gastrointestinal AEs, specifically nausea, only occurred in 1 patient. Hypertension occurred in 25 treatment regimens (16.8%) for 21 unique patients (4 BP elevations occurred in 1 patient on 4 different regimens). However, the retrospective nature of reporting may limit accurate assessment. A closer analysis determined that elevated BP readings correlated with elevated pain scores at the time of the readings, which could have factored into the BP elevations. However, ongoing monitoring is needed due to an increased risk of hypertension, particularly given recent FDA labeling updates for CGRP-targeting therapies including gepants. In light of this, and the overall low incidence of hypertension reported, no new safety concerns were identified.

Limitations

Efficacy data in this project were exploratory. This evaluation did not show a significant difference in migraine intensity or duration after adding a gepant for acute treatment. The study was not powered to detect a significant difference. Limited data exist assessing efficacy outcomes with dual CGRP-targeting treatment regimens. The COURAGE study assessed the real-world effectiveness of ubrogepant and CGRP mAbs with or without the addition of onabotulinumtoxinA. The final analysis of the ubrogepant and CGRP mAb arm included 245 total patients and assessed meaningful migraine pain relief, restoration of normal function after a migraine, and treatment satisfaction. By hour 2, 61.6% of patients reported achieving migraine pain relief, rising to 80.4% by hour 4. Return to normal function occurred in 34.7% at hour 2 and 55.5% by hour 4.¹³ The long-term safety and efficacy of combining erenumab and rimegepant were described in a case series involving 2 patients. Both patients reported that the concomitant CGRP-targeted therapies were effective and reported no AEs.¹⁴

The retrospective design of this study meant that there was potential for limited documentation and introduction of bias into the results. Data were collected at a single VA health care system, and thus, results may not be generalizable to a broader population. However, the study population was consistent with the higher incidence of migraine expected in females in the general population. The sample size was limited, particularly in the exploratory efficacy endpoint assessment.

Limitations were observed due to inconsistent documentation regarding headache characteristics, making it challenging to draw meaningful conclusions from this data set. Additional confounding factors, including polypharmacy, nonadherence to medications, and comorbidities, may have skewed results. For example, while our study design required that the preventive CGRP-targeting medication be stable for 12 weeks for inclusion in further efficacy analysis, other medications commonly used for migraine prevention may have been adjusted (which was not accounted for in this analysis). Given this, more large-scale, placebo-controlled, randomized studies are needed to continue to assess the safety and efficacy of these combination treatment regimens.

Conclusions

Few AEs or safety events were reported with combination CGRP-targeting treatment for acute and preventive treatment of migraine. Those that were identified were considered mild. Efficacy data were limited, and further studies are needed to fully assess outcomes.

Calcitonin gene-related peptide (CGRP) is a neuropeptide that plays a key role in migraine pathophysiology by promoting the dilation of cerebral blood vessels and transmitting pain signals.¹ CGRP has generated interest for the prevention and acute treatment of migraine. Since 2018, 8 novel CGRP-targeting therapies have been approved by the US Food and Drug Administration (FDA) for the management of migraines.^2,3 For migraine prevention, there are 4 injectable monoclonal antibodies (mAbs) directed against the CGRP receptor (erenumab) or the CGRP ligand (fremanezumab, galcanezumab, and eptinezumab). There are also 2 oral small-molecule CGRP receptor antagonists, termed gepants, that also are approved for migraine prevention (atogepant and rimegepant). Three gepants are approved for acute migraine treatment and are administered orally (rimegepant and ubrogepant) or intranasally (zavegepant) (Table 1).

CGRP-targeting therapies have received attention for their role in vasodilation within the cerebral, coronary, and renal vasculature.⁴ CGRP-mediated vasodilatory effects cause systemic regulation of blood pressure (BP) and play a protective role in hypertension.² Some studies, particularly with erenumab, have shown that the inhibitory role of the agent leads to an increase in BP, as well as gastrointestinal issues such as constipation.^2,5 The FDA recently updated monitoring recommendations for all CGRP-targeting therapies to include the potential for BP elevations and hypertension. Outside of this, there is no definitive evidence linking dual CGRP-targeted therapy to higher cardiovascular or gastrointestinal risks and prescribing information does not carry contraindications.⁶

In a 2021 consensus statement, the American Headache Society (AHS) recommended CGRP-targeting therapies for migraine prevention after inability to tolerate or inadequate response to an 8-week trial of ≥ 2 drug classes including antihypertensives, antiseizure medications, antidepressants, and onabotulinumtoxinA.⁷ For acute treatment, AHS recommended gepant use after contraindication to or inadequate response to ≥ 2 triptans. Guidance on combination CGRP-targeting therapies for both prevention and acute treatment was not provided.⁷ More recently, the AHS published a position statement noting substantial efficacy and safety data for CGRP-targeting therapies and suggested its consideration as a first-line option for migraine prevention, though use for acute treatment or combination CGRP-targeting therapies for both prevention and acute treatment were not addressed.⁸

The International Headache Society guidelines for the acute treatment of migraines recommend nonopioid analgesics as first-line therapy for mild migraine attacks. For moderate to severe attacks, triptans with or without a nonopioid analgesic were recommended as first-line therapy, prior to consideration of CGRP-targeted therapy.⁹ The increased use of this new drug class has also led to combination use of CGRP-targeting therapies for migraine prevention and acute treatment as seen in clinical practice and reflected by some case reports, case series, and small studies describing such use.^10-14 In light of the similar mechanism of action of these therapies and the physiologic role of CGRP, there have been calls for safety evaluation.¹⁵

To our knowledge, no studies have evaluated dual CGRP-targeting regimens for migraine in the veteran population. In 2023, the US Department of Veterans Affairs (VA) and US Department of Defense (DoD) updated their clinical practice guidelines for the management of headache.³ For migraine prevention, the VA/DoD guidelines include a strong recommendation for the use of erenumab, fremanezumab, and galcanezumab; a weak recommendation for the use of atogepant; and a recommendation neither for nor against the use of rimegepant. For acute treatment, the guidelines assign a weak recommendation for the use of rimegepant and ubrogepant. Combination use was not addressed.³

Prior to the VA/DoD guidelines, the Veterans Health Administration restricted the dual use of CGRP-targeting therapies for both preventive and acute migraine treatment. However, the VA Pharmacy Benefit Management Service removed the restriction in the Criteria for Use documents, allowing broader access to these medications for veterans.^16-22 This change permits the use of CGRP-targeting drugs for both acute and preventive migraine treatment after initial data reflecting real-world case reports and open-label studies suggested possible efficacy without a clear safety concern.^11,12 This study aims to fill the gap in the literature by evaluating the safety, efficacy, and overall outcomes of combination CGRP-targeting treatment for migraine prevention and acute treatment in a veteran population.

Methods

This single-center, retrospective, medication use evaluation at the Ralph H. Johnson VA Medical Center (RHJVAMC) was reviewed by the RHJVAMC Research and Development Committee and Quality Improvement Program Evaluation Self Certification Tool, which both determined that institutional review board approval was not required because it was considered part of routine care and quality improvement. Computerized Patient Record System (CPRS) data were reviewed between April 1, 2023 (after the Criteria for Use for CGRP-targeting therapies was updated), through January 31, 2025. Patients were included if they had a confirmed diagnosis of migraine using the International Classification of Headache Disorders, 3rd edition criteria and had concomitant active prescriptions for both a preventive and acute treatment CGRP-targeting agent during the project period.²³ Only patients receiving care from the RHJVAMC neurology department were included.

The primary objective was to assess the safety of dual CGRP-targeting therapies for migraine treatment. Key safety endpoints included effects on liver function, kidney function, and BP. Safety outcomes were graded using Common Terminology Criteria for Adverse Events.²⁴ Changes in liver function were categorized as grade 1, 2, or 3 elevations: grade 1 (aspartate aminotransferase [AST]/alanine aminotransferase [ALT] up to 3x the upper limit of normal [ULN] or bilirubin > 1.5 x ULN); grade 2 (AST/ALT 3-6 x ULN or bilirubin 1.5-3 x ULN); and grade 3 (AST/ALT 5-10 x ULN or bilirubin 3-10 x ULN). Kidney function changes were assessed by serum creatinine levels using a similar grading system: Grade 1 (≤ 1.5 x ULN); grade 2 (1.5-3 x baseline of normal); and grade 3 (3-6 x ULN or baseline). Changes in BP were monitored from baseline to the time of the first neurology follow-up. Elevations were grouped into 2 categories, defined as BP ≥ 140 mm Hg systolic and/or 90 mm Hg diastolic (category 1) and ≥ 160 mm Hg systolic and/or 100 mm Hg diastolic (category 2). Neurology documentation was also reviewed in CPRS for individual patient-reported adverse effects (AEs). Safety endpoints were tracked for any occurrence during the project period.

The secondary objective was to describe the patient-reported efficacy of adding a gepant for acute migraine treatment to existing CGRP-targeting therapies for migraine prevention, in those patients who were stable for ≥ 12 weeks on the preventive therapy. Neurology documentation of headache characteristics, including headache severity as rated on a numerical pain score from 0 (no pain) to 10 (worst pain), and duration of headaches (in hours) were recorded during the project period. Changes in headache characteristics were tracked from baseline (ie, the neurology visit when the gepant was first requested) to the first neurology follow-up within 6 months of initiating gepant for acute treatment. If ranges were provided within documentation, a mean was calculated and used for data collection. Neurology documentation was also reviewed for any patient report of overall effectiveness with the added gepant, and categorized as symptoms improved, worsened, or did not change based on subjective report. Descriptive statistics were used for data analysis. A 1-sample Wilcoxon signed rank test was performed as an exploratory analysis for change in headache characteristics from baseline to first neurology follow-up within 6 months. Each individual CGRP regimen was counted as a unique data point to adequately describe changes associated with each new medication and/or dose adjustment. Therefore, patients could be included more than once to account for each distinct treatment regimen.

Results

From April 1, 2023, to January 31, 2025, 96 patients were identified with active prescriptions for dual CGRP-targeting therapies. Of the 96 patients, 89 were included in the final analysis; 1 patient lacked a migraine diagnosis and 6 did not have a concomitant dual CGRP-targeted regimen and were excluded. The mean age of patients was 46.8 years and 54 (61%) were female. The most common migraine diagnosis was chronic migraine in 68 patients (76%). Triptans, ibuprofen, and acetaminophen were the most commonly used acute treatment medications (Table 2).

Safety Assessment

Many of the 89 unique patients trialed > 1 regimen. Thus, for the safety analysis, we analyzed 149 patients on unique dual CGRP-targeting regimens (Table 3). Ubrogepant was used by 126 patients (84.6%) for acute treatment. For preventive therapy, 63 patients (42.3%) used erenumab injections and 55 (36.9%) used fremanezumab injections. Seven patients (4.7%) reported AEs (Table 4). Five of the 7 AEs were noted in the package inserts.^25-32 One patient taking both atogepant and ubrogepant reported brain fog that resolved after a dose reduction of atogepant to every other day dosing. A patient taking fremanezumab and rimegepant reported myalgia/joint pain after the first fremanezumab injection, which resolved after a few days and did not recur during the study period.

Nine of 149 patient regimens (6.0%) were associated with changes in liver function tests or serum creatinine, though all but 1 were grade 1 (1 patient had a grade 2 ALT elevation). Twenty-five patients (16.8%) experienced changes in BP, most of which were category 1 elevations. Four patients had systolic or diastolic BP ≥ 160 mm Hg or 100 mm Hg, respectively (Table 5).

Efficacy Assessment

Of the 149 unique dual CGRP regimens, 59 were eligible for the exploratory efficacy analysis. Data were excluded from the efficacy analysis if patients had not been on a stable CGRP preventive migraine regimen for ≥ 12 weeks prior to the addition of a gepant. Fourteen regimens were excluded due to a lack of clear documentation on efficacy, leaving 45 analyzed regimens. Of the 45 regimens, 34 were from unique patients. There was no median change in migraine intensity or duration found in the efficacy analysis (0.0, P = .18, and 0.0, P = .92, respectively). Ten patients on dual CGRP therapy reported that the addition of a gepant for acute treatment improved their symptoms, 20 reported that their symptoms were unchanged and/or worsened, and 29 lacked documentation.

Discussion

This study aimed to describe the safety and efficacy of concomitant CGRP regimens for migraine prevention and acute treatment. To our knowledge, this was the first descriptive study of these agents in a veteran population. The potential for increased AEs with concomitant use of CGRP antagonists is due to the similarities in the mechanism of action between the agents, which both target the same receptor/ligand pathway. Given CGRP activity in both the gastrointestinal and cardiovascular systems, the potential for related AEs is speculative. Patient-reported AEs occurred in 7 of 149 unique treatment regimens reviewed for an incidence rate < 5%. All AEs were nonserious and self-limiting.

Our findings are consistent with available research. A 2024 retrospective, exploratory real-world study evaluating the safety and tolerability of combining CGRP-targeting mAbs with gepants reported findings consistent with our results. This analysis included adult patients treated with ≥ 1 previous anti-CGRP mAb and found that 234 of 516 patients included received a combination of a gepant in addition to a CGRP-targeting mAb. Of these 234 patients, 1.3% reported nonserious AEs.³³ Similarly, in a multicenter, open-label, long-term safety study in adults experiencing multiple monthly migraine attacks, a subgroup of 13 participants taking a stable dose of an anti-CGRP mAb also took rimegepant 75 mg as needed for acute treatment for 12 weeks. These patients experienced no serious AEs or any AEs leading to discontinuation.¹⁴ A study evaluating the drug-drug interaction, safety, and tolerability of dual therapy (atogepant 60 mg daily and ubrogepant 100 mg every 3 days) in 26 patients found no serious AEs, including no significant changes from baseline in laboratory results, vital signs, or safety-related 12-lead electrocardiogram parameters.¹⁵The TANDEM real-world, open-label, prospective study demonstrated similar results. It evaluated the safety and tolerability of concomitant use of ubrogepant and atogepant in patients with episodic migraines and found no increase in AEs when comparing atogepant alone with combination therapy. Twenty-six patients (9.9%) discontinued treatment due to AEs. The most common treatment-related AEs were constipation, nausea, decreased appetite, and fatigue. Efficacy data were also noted to be an exploratory endpoint in the TANDEM study; however, results have not been published.¹²

Within this safety analysis, new onset gastrointestinal AEs, specifically nausea, only occurred in 1 patient. Hypertension occurred in 25 treatment regimens (16.8%) for 21 unique patients (4 BP elevations occurred in 1 patient on 4 different regimens). However, the retrospective nature of reporting may limit accurate assessment. A closer analysis determined that elevated BP readings correlated with elevated pain scores at the time of the readings, which could have factored into the BP elevations. However, ongoing monitoring is needed due to an increased risk of hypertension, particularly given recent FDA labeling updates for CGRP-targeting therapies including gepants. In light of this, and the overall low incidence of hypertension reported, no new safety concerns were identified.

Limitations

Efficacy data in this project were exploratory. This evaluation did not show a significant difference in migraine intensity or duration after adding a gepant for acute treatment. The study was not powered to detect a significant difference. Limited data exist assessing efficacy outcomes with dual CGRP-targeting treatment regimens. The COURAGE study assessed the real-world effectiveness of ubrogepant and CGRP mAbs with or without the addition of onabotulinumtoxinA. The final analysis of the ubrogepant and CGRP mAb arm included 245 total patients and assessed meaningful migraine pain relief, restoration of normal function after a migraine, and treatment satisfaction. By hour 2, 61.6% of patients reported achieving migraine pain relief, rising to 80.4% by hour 4. Return to normal function occurred in 34.7% at hour 2 and 55.5% by hour 4.¹³ The long-term safety and efficacy of combining erenumab and rimegepant were described in a case series involving 2 patients. Both patients reported that the concomitant CGRP-targeted therapies were effective and reported no AEs.¹⁴

The retrospective design of this study meant that there was potential for limited documentation and introduction of bias into the results. Data were collected at a single VA health care system, and thus, results may not be generalizable to a broader population. However, the study population was consistent with the higher incidence of migraine expected in females in the general population. The sample size was limited, particularly in the exploratory efficacy endpoint assessment.

Limitations were observed due to inconsistent documentation regarding headache characteristics, making it challenging to draw meaningful conclusions from this data set. Additional confounding factors, including polypharmacy, nonadherence to medications, and comorbidities, may have skewed results. For example, while our study design required that the preventive CGRP-targeting medication be stable for 12 weeks for inclusion in further efficacy analysis, other medications commonly used for migraine prevention may have been adjusted (which was not accounted for in this analysis). Given this, more large-scale, placebo-controlled, randomized studies are needed to continue to assess the safety and efficacy of these combination treatment regimens.

Conclusions

Few AEs or safety events were reported with combination CGRP-targeting treatment for acute and preventive treatment of migraine. Those that were identified were considered mild. Efficacy data were limited, and further studies are needed to fully assess outcomes.

Seeking to modernize treatment for traumatic brain injury (TBI), Reps. Jack Bergman (R-MI) and Sarah Elfreth (D-MD) introduced the bipartisan BEACON Act to Congress on January 9. The legislation aims to expand access to innovative, evidence-based, nonpharmacological therapies to treat TBI beyond medication-centered approaches that do not always address the long-term and individualized needs of these veterans. These current methods leave “gaps in recovery, wellness, and post-service outcomes,” Bergman and Elfreth argued.

During a March 5 House Committee on Veterans’ Affairs Subcommittee on Health hearing, discussion centered on the proposed BEACON Act, as well as the additional challenges Neurology Centers of Excellence (CoEs) face to address TBI in veterans.

The act proposes awarding $60 million in grants over 3 years to private entities for TBI treatment and research and establishing 2 US Department of Veterans Affairs (VA) grant programs. The TBI Innovation Grant Program would support clinical studies and partnerships between community health care institutions, academic institutions, and the VA. The Independent Research Grant Program would advance third-party research and “implementation of proven alternative treatments,” with oversight by an independent entity modeled after the VA National Center for PTSD.

The proposed legislation has drawn criticism. “I do not disagree that veterans may need support from several different avenues to support their recovery journeys and I don't discount the role that nonprofits and academic affiliates play in facilitating and supporting that care,” said Ranking Member Rep. Julia Brownley (D-CA) said. “However, I need to draw the line at legislation that will take money from existing VA programs and redirect it to outside organizations and providers to do essentially the very same thing VA is already doing.” 

Russell Gore, MD, a neurologist and chief medical officer of Avalon Action Alliance, called VA TBI care fragmented and said the BEACON Act offers an opportunity to enhance it.

“This legislation is designed to evaluate effective treatments and leverage civilian and academic TBI expertise that is aligned with the VA’s mission,” he said. “This is not an attempt to privatize care, but to complement VA research and clinical capacity… With smart, coordinated partnerships and targeted investment, we can reach more veterans earlier, treat them more effectively.”

The VA has 5 polytrauma rehabilitation centers, 23 polytrauma network sites, and numerous clinics supporting > 110 TBI teams. It also has 42 CoEs related to neurology. 

In a prepared statement, Glenn Graham, MD, PhD, retired Executive Director of the VA’s Neurology Clinical Programs representing the Association of VA Neurology Services cited the CoEs’ contribution to standardization of care. “Without systemwide coordination, practice patterns can vary. A veteran in a rural facility should receive the same standard of neurological assessment and management as a veteran treated in one of our flagship medical centers,” he said, before highlighting the capabilities of tele-neurology, electronic consultation, and remote interpretation of diagnostic studies to reduce travel burdens and promote equity in access. 

Graham cautioned, though, that the CoEs face challenges with budgeting and recent VA reductions in force. The proposed legislation, Graham said, would use VA appropriations to fund extramural research and “could drain vital resources from ongoing research, training and clinical programs, diverting funds to institutions with uncertain track records and limited experience working with the veteran population.” 

Several people highlighted the world-renowned research coming out of the VA, efforts that both veterans and the general public endorse.

Russell Lemle, former chief psychologist for the San Francisco VA Healthcare System and a senior policy analyst at the Veterans Healthcare Policy Institute, wrote with Jasper Craven: “The private sector has nothing commensurate with this level of care. And yet this bill would push TBI treatment out to private grantees, part of the accelerating movement to privatize the entire VA—even its signature, best-in-class programs.

“The act aims to divert resources from the VA’s world-class TBI and PTSD programs by creating a parallel treatment framework.”

Gore, however, said the Avalon Action Alliance supports a “fill-the-void” approach of “capacity augmentation, not privatization.”

“The intent is to complement VA by partnering with high-performing programs capable of delivering comprehensive assessment, interdisciplinary treatment, and structured follow-up for veterans who are not effectively reached (or not successfully retained) within traditional pathways,” he said.

Seeking to modernize treatment for traumatic brain injury (TBI), Reps. Jack Bergman (R-MI) and Sarah Elfreth (D-MD) introduced the bipartisan BEACON Act to Congress on January 9. The legislation aims to expand access to innovative, evidence-based, nonpharmacological therapies to treat TBI beyond medication-centered approaches that do not always address the long-term and individualized needs of these veterans. These current methods leave “gaps in recovery, wellness, and post-service outcomes,” Bergman and Elfreth argued.

During a March 5 House Committee on Veterans’ Affairs Subcommittee on Health hearing, discussion centered on the proposed BEACON Act, as well as the additional challenges Neurology Centers of Excellence (CoEs) face to address TBI in veterans.

The act proposes awarding $60 million in grants over 3 years to private entities for TBI treatment and research and establishing 2 US Department of Veterans Affairs (VA) grant programs. The TBI Innovation Grant Program would support clinical studies and partnerships between community health care institutions, academic institutions, and the VA. The Independent Research Grant Program would advance third-party research and “implementation of proven alternative treatments,” with oversight by an independent entity modeled after the VA National Center for PTSD.

The proposed legislation has drawn criticism. “I do not disagree that veterans may need support from several different avenues to support their recovery journeys and I don't discount the role that nonprofits and academic affiliates play in facilitating and supporting that care,” said Ranking Member Rep. Julia Brownley (D-CA) said. “However, I need to draw the line at legislation that will take money from existing VA programs and redirect it to outside organizations and providers to do essentially the very same thing VA is already doing.” 

Russell Gore, MD, a neurologist and chief medical officer of Avalon Action Alliance, called VA TBI care fragmented and said the BEACON Act offers an opportunity to enhance it.

“This legislation is designed to evaluate effective treatments and leverage civilian and academic TBI expertise that is aligned with the VA’s mission,” he said. “This is not an attempt to privatize care, but to complement VA research and clinical capacity… With smart, coordinated partnerships and targeted investment, we can reach more veterans earlier, treat them more effectively.”

The VA has 5 polytrauma rehabilitation centers, 23 polytrauma network sites, and numerous clinics supporting > 110 TBI teams. It also has 42 CoEs related to neurology. 

In a prepared statement, Glenn Graham, MD, PhD, retired Executive Director of the VA’s Neurology Clinical Programs representing the Association of VA Neurology Services cited the CoEs’ contribution to standardization of care. “Without systemwide coordination, practice patterns can vary. A veteran in a rural facility should receive the same standard of neurological assessment and management as a veteran treated in one of our flagship medical centers,” he said, before highlighting the capabilities of tele-neurology, electronic consultation, and remote interpretation of diagnostic studies to reduce travel burdens and promote equity in access. 

Graham cautioned, though, that the CoEs face challenges with budgeting and recent VA reductions in force. The proposed legislation, Graham said, would use VA appropriations to fund extramural research and “could drain vital resources from ongoing research, training and clinical programs, diverting funds to institutions with uncertain track records and limited experience working with the veteran population.” 

Several people highlighted the world-renowned research coming out of the VA, efforts that both veterans and the general public endorse.

Russell Lemle, former chief psychologist for the San Francisco VA Healthcare System and a senior policy analyst at the Veterans Healthcare Policy Institute, wrote with Jasper Craven: “The private sector has nothing commensurate with this level of care. And yet this bill would push TBI treatment out to private grantees, part of the accelerating movement to privatize the entire VA—even its signature, best-in-class programs.

“The act aims to divert resources from the VA’s world-class TBI and PTSD programs by creating a parallel treatment framework.”

Gore, however, said the Avalon Action Alliance supports a “fill-the-void” approach of “capacity augmentation, not privatization.”

“The intent is to complement VA by partnering with high-performing programs capable of delivering comprehensive assessment, interdisciplinary treatment, and structured follow-up for veterans who are not effectively reached (or not successfully retained) within traditional pathways,” he said.

Seeking to modernize treatment for traumatic brain injury (TBI), Reps. Jack Bergman (R-MI) and Sarah Elfreth (D-MD) introduced the bipartisan BEACON Act to Congress on January 9. The legislation aims to expand access to innovative, evidence-based, nonpharmacological therapies to treat TBI beyond medication-centered approaches that do not always address the long-term and individualized needs of these veterans. These current methods leave “gaps in recovery, wellness, and post-service outcomes,” Bergman and Elfreth argued.

During a March 5 House Committee on Veterans’ Affairs Subcommittee on Health hearing, discussion centered on the proposed BEACON Act, as well as the additional challenges Neurology Centers of Excellence (CoEs) face to address TBI in veterans.

The act proposes awarding $60 million in grants over 3 years to private entities for TBI treatment and research and establishing 2 US Department of Veterans Affairs (VA) grant programs. The TBI Innovation Grant Program would support clinical studies and partnerships between community health care institutions, academic institutions, and the VA. The Independent Research Grant Program would advance third-party research and “implementation of proven alternative treatments,” with oversight by an independent entity modeled after the VA National Center for PTSD.

The proposed legislation has drawn criticism. “I do not disagree that veterans may need support from several different avenues to support their recovery journeys and I don't discount the role that nonprofits and academic affiliates play in facilitating and supporting that care,” said Ranking Member Rep. Julia Brownley (D-CA) said. “However, I need to draw the line at legislation that will take money from existing VA programs and redirect it to outside organizations and providers to do essentially the very same thing VA is already doing.” 

Russell Gore, MD, a neurologist and chief medical officer of Avalon Action Alliance, called VA TBI care fragmented and said the BEACON Act offers an opportunity to enhance it.

“This legislation is designed to evaluate effective treatments and leverage civilian and academic TBI expertise that is aligned with the VA’s mission,” he said. “This is not an attempt to privatize care, but to complement VA research and clinical capacity… With smart, coordinated partnerships and targeted investment, we can reach more veterans earlier, treat them more effectively.”

The VA has 5 polytrauma rehabilitation centers, 23 polytrauma network sites, and numerous clinics supporting > 110 TBI teams. It also has 42 CoEs related to neurology. 

In a prepared statement, Glenn Graham, MD, PhD, retired Executive Director of the VA’s Neurology Clinical Programs representing the Association of VA Neurology Services cited the CoEs’ contribution to standardization of care. “Without systemwide coordination, practice patterns can vary. A veteran in a rural facility should receive the same standard of neurological assessment and management as a veteran treated in one of our flagship medical centers,” he said, before highlighting the capabilities of tele-neurology, electronic consultation, and remote interpretation of diagnostic studies to reduce travel burdens and promote equity in access. 

Graham cautioned, though, that the CoEs face challenges with budgeting and recent VA reductions in force. The proposed legislation, Graham said, would use VA appropriations to fund extramural research and “could drain vital resources from ongoing research, training and clinical programs, diverting funds to institutions with uncertain track records and limited experience working with the veteran population.” 

Several people highlighted the world-renowned research coming out of the VA, efforts that both veterans and the general public endorse.

Russell Lemle, former chief psychologist for the San Francisco VA Healthcare System and a senior policy analyst at the Veterans Healthcare Policy Institute, wrote with Jasper Craven: “The private sector has nothing commensurate with this level of care. And yet this bill would push TBI treatment out to private grantees, part of the accelerating movement to privatize the entire VA—even its signature, best-in-class programs.

“The act aims to divert resources from the VA’s world-class TBI and PTSD programs by creating a parallel treatment framework.”

Gore, however, said the Avalon Action Alliance supports a “fill-the-void” approach of “capacity augmentation, not privatization.”

“The intent is to complement VA by partnering with high-performing programs capable of delivering comprehensive assessment, interdisciplinary treatment, and structured follow-up for veterans who are not effectively reached (or not successfully retained) within traditional pathways,” he said.

On January 8, 2020, Iran fired 15 ballistic missiles at the Al-Asad Airbase, where Alan Johnson, an Army Lieutenant Colonel and Aeromedical Physician Assistant, was deployed.

“I have no memory of the first 3 missile impacts because the third missile impact knocked me unconscious,” Johnson said in a statement to a House Committee on Veterans’ Affairs subcommittee on Health in a March 5 hearing. “I woke up just in time to experience missiles 4, 5, and 6.”

March is Brain Injury Awareness month, highlighting how nearly 1 in 4 veterans has screened positive for probable traumatic brain injury (TBI). Veterans with TBI also have a higher risk of suicide: in 2023, the suicide rate for veterans with a recent TBI diagnosis was > 94% higher than for veterans without a TBI diagnosis.

“For many veterans, TBI is not a single episode of care; it is a chronic neurological condition requiring coordinated, longitudinal management,” Glenn D. Graham, MD, PhD, president of the Association of VA Neurology Service (AVANS) and former executive director of the US Department of Veterans Affairs (VA) Neurology Clinical Programs said in a statement. “TBI is neurologically complex and often intertwined with other conditions … Accurate diagnosis and effective treatment require subspecialty expertise in areas such as epilepsy, headache medicine, and neurodegenerative disease. The Centers of Excellence (CoE) ensure that this expertise is available across our national system.”

An estimated 25% of service members who have been hospitalized with TBI will develop long-term disability. Studies show direct links between TBI and the development of neurological disorders. Lt. Col. Johnson, for instance, has been diagnosed with posttraumatic stress disorder, cranial nerve damage, double vision, chronic insomnia, ringing in the ears, neck pain, balance problems, difficulty in word finding, and depression. After 37 years in emergency medicine, Johnson said, he had to “bench” himself due to the sequelae: “I can’t do what I love to do anymore.”

However, many service members may not be diagnosed correctly. Blast-related brain injuries may be delayed, subtle, and easily missed in combat environments. In research Johnson coauthored, > 20% of troops were diagnosed with mild TBIs 4 weeks after the attack. Moreover, he said, soldiers being screened may underreport their symptoms in order to return to duty.

Timely diagnosis is key, but so is consistent follow-up. Ranking Member Rep. Julia Brownley (D-CA) said, “TBI is not an illness that goes away with medicine … It is a long-term chronic condition for which many veterans need ongoing integrated and well-coordinated care.”

The Veterans Health Administration (VHA) has 5 polytrauma rehabilitation centers, 23 polytrauma network sites, numerous polytrauma support clinics, and > 110 TBI teams. Rachel McArdle, deputy executive director of rehabilitation and prosthetic services at VHA, told the subcommittee that since 2007, VHA has screened 1.8 million veterans for TBI. Every veteran, she said, receives an individualized plan addressing physical, cognitive, and emotional needs, often integrated with mental health services and patient-centered care approaches.

Graham and others expressed concern that despite their importance, the CoEs faced daunting challenges.

“Budgets have generally increased in recent years, but often unpredictably,” Graham noted. “Due to the recent focus on downsizing VHA staffing, a number of key positions are currently vacant due to clinical and administrative staff reassignment, resignation to accept positions outside VHA, or opting for early or standard retirement.”

In a statement, Natalia S. Rost, MD, MPH, President of the American Academy of Neurology, urged Congress to continue to provide funds for Neurology CoEs: “We look forward to continuing to work with Congress to secure robust, sustained funding to ensure our nation’s veterans receive the highest quality of neurologic care for years to come.”

Joel Scholten, MD, VA Executive Director of Physical Medicine and Rehabilitation, told the panel that the VA Office of Research and Development allocated $50 million for fiscal year 2025 research projects on TBI. Some are aimed at developing better biomarkers not only for TBI but also co-occurring mental health diagnoses. “As we work to better understand and better identify biomarkers not only for TBI but also looking at those associated or affiliated risk factors that can enhance suicide risk, we'll better be able to care for veterans.”

“I’m confident that the VA has all the data, legal authority, and funding it needs to effectively treat TBI,” Rep. Mariannette Miller-Meeks (R-IA), subcommittee chair, added. “Here's where I’ve seen the VA needs improvement: Consistent quality in patient care and data.”

Still, Graham argued that staffing reductions may be straining VHA’s ability to continue its mission. Anxiety about job security, increased vacancies, inadequate space in overcrowded VA medical centers due to the return to office mandate, and the loss of psychological safety and a positive workplace culture threatened the quality of neurology care at VHA.

“The VHA has long promoted the path to becoming a high reliability organization, with an obsessive attention to accuracy and avoidance of clinical errors, in a climate of psychological safety that encourages reporting of mistakes and ‘near misses’ in a concerted effort to prevent patient harm,” he argued. “Unfortunately, these principles appear to be in abeyance at present.”

On January 8, 2020, Iran fired 15 ballistic missiles at the Al-Asad Airbase, where Alan Johnson, an Army Lieutenant Colonel and Aeromedical Physician Assistant, was deployed.

“I have no memory of the first 3 missile impacts because the third missile impact knocked me unconscious,” Johnson said in a statement to a House Committee on Veterans’ Affairs subcommittee on Health in a March 5 hearing. “I woke up just in time to experience missiles 4, 5, and 6.”

March is Brain Injury Awareness month, highlighting how nearly 1 in 4 veterans has screened positive for probable traumatic brain injury (TBI). Veterans with TBI also have a higher risk of suicide: in 2023, the suicide rate for veterans with a recent TBI diagnosis was > 94% higher than for veterans without a TBI diagnosis.

“For many veterans, TBI is not a single episode of care; it is a chronic neurological condition requiring coordinated, longitudinal management,” Glenn D. Graham, MD, PhD, president of the Association of VA Neurology Service (AVANS) and former executive director of the US Department of Veterans Affairs (VA) Neurology Clinical Programs said in a statement. “TBI is neurologically complex and often intertwined with other conditions … Accurate diagnosis and effective treatment require subspecialty expertise in areas such as epilepsy, headache medicine, and neurodegenerative disease. The Centers of Excellence (CoE) ensure that this expertise is available across our national system.”

An estimated 25% of service members who have been hospitalized with TBI will develop long-term disability. Studies show direct links between TBI and the development of neurological disorders. Lt. Col. Johnson, for instance, has been diagnosed with posttraumatic stress disorder, cranial nerve damage, double vision, chronic insomnia, ringing in the ears, neck pain, balance problems, difficulty in word finding, and depression. After 37 years in emergency medicine, Johnson said, he had to “bench” himself due to the sequelae: “I can’t do what I love to do anymore.”

However, many service members may not be diagnosed correctly. Blast-related brain injuries may be delayed, subtle, and easily missed in combat environments. In research Johnson coauthored, > 20% of troops were diagnosed with mild TBIs 4 weeks after the attack. Moreover, he said, soldiers being screened may underreport their symptoms in order to return to duty.

Timely diagnosis is key, but so is consistent follow-up. Ranking Member Rep. Julia Brownley (D-CA) said, “TBI is not an illness that goes away with medicine … It is a long-term chronic condition for which many veterans need ongoing integrated and well-coordinated care.”

The Veterans Health Administration (VHA) has 5 polytrauma rehabilitation centers, 23 polytrauma network sites, numerous polytrauma support clinics, and > 110 TBI teams. Rachel McArdle, deputy executive director of rehabilitation and prosthetic services at VHA, told the subcommittee that since 2007, VHA has screened 1.8 million veterans for TBI. Every veteran, she said, receives an individualized plan addressing physical, cognitive, and emotional needs, often integrated with mental health services and patient-centered care approaches.

Graham and others expressed concern that despite their importance, the CoEs faced daunting challenges.

“Budgets have generally increased in recent years, but often unpredictably,” Graham noted. “Due to the recent focus on downsizing VHA staffing, a number of key positions are currently vacant due to clinical and administrative staff reassignment, resignation to accept positions outside VHA, or opting for early or standard retirement.”

In a statement, Natalia S. Rost, MD, MPH, President of the American Academy of Neurology, urged Congress to continue to provide funds for Neurology CoEs: “We look forward to continuing to work with Congress to secure robust, sustained funding to ensure our nation’s veterans receive the highest quality of neurologic care for years to come.”

Joel Scholten, MD, VA Executive Director of Physical Medicine and Rehabilitation, told the panel that the VA Office of Research and Development allocated $50 million for fiscal year 2025 research projects on TBI. Some are aimed at developing better biomarkers not only for TBI but also co-occurring mental health diagnoses. “As we work to better understand and better identify biomarkers not only for TBI but also looking at those associated or affiliated risk factors that can enhance suicide risk, we'll better be able to care for veterans.”

“I’m confident that the VA has all the data, legal authority, and funding it needs to effectively treat TBI,” Rep. Mariannette Miller-Meeks (R-IA), subcommittee chair, added. “Here's where I’ve seen the VA needs improvement: Consistent quality in patient care and data.”

Still, Graham argued that staffing reductions may be straining VHA’s ability to continue its mission. Anxiety about job security, increased vacancies, inadequate space in overcrowded VA medical centers due to the return to office mandate, and the loss of psychological safety and a positive workplace culture threatened the quality of neurology care at VHA.

“The VHA has long promoted the path to becoming a high reliability organization, with an obsessive attention to accuracy and avoidance of clinical errors, in a climate of psychological safety that encourages reporting of mistakes and ‘near misses’ in a concerted effort to prevent patient harm,” he argued. “Unfortunately, these principles appear to be in abeyance at present.”

On January 8, 2020, Iran fired 15 ballistic missiles at the Al-Asad Airbase, where Alan Johnson, an Army Lieutenant Colonel and Aeromedical Physician Assistant, was deployed.

“I have no memory of the first 3 missile impacts because the third missile impact knocked me unconscious,” Johnson said in a statement to a House Committee on Veterans’ Affairs subcommittee on Health in a March 5 hearing. “I woke up just in time to experience missiles 4, 5, and 6.”

March is Brain Injury Awareness month, highlighting how nearly 1 in 4 veterans has screened positive for probable traumatic brain injury (TBI). Veterans with TBI also have a higher risk of suicide: in 2023, the suicide rate for veterans with a recent TBI diagnosis was > 94% higher than for veterans without a TBI diagnosis.

“For many veterans, TBI is not a single episode of care; it is a chronic neurological condition requiring coordinated, longitudinal management,” Glenn D. Graham, MD, PhD, president of the Association of VA Neurology Service (AVANS) and former executive director of the US Department of Veterans Affairs (VA) Neurology Clinical Programs said in a statement. “TBI is neurologically complex and often intertwined with other conditions … Accurate diagnosis and effective treatment require subspecialty expertise in areas such as epilepsy, headache medicine, and neurodegenerative disease. The Centers of Excellence (CoE) ensure that this expertise is available across our national system.”

An estimated 25% of service members who have been hospitalized with TBI will develop long-term disability. Studies show direct links between TBI and the development of neurological disorders. Lt. Col. Johnson, for instance, has been diagnosed with posttraumatic stress disorder, cranial nerve damage, double vision, chronic insomnia, ringing in the ears, neck pain, balance problems, difficulty in word finding, and depression. After 37 years in emergency medicine, Johnson said, he had to “bench” himself due to the sequelae: “I can’t do what I love to do anymore.”

However, many service members may not be diagnosed correctly. Blast-related brain injuries may be delayed, subtle, and easily missed in combat environments. In research Johnson coauthored, > 20% of troops were diagnosed with mild TBIs 4 weeks after the attack. Moreover, he said, soldiers being screened may underreport their symptoms in order to return to duty.

Timely diagnosis is key, but so is consistent follow-up. Ranking Member Rep. Julia Brownley (D-CA) said, “TBI is not an illness that goes away with medicine … It is a long-term chronic condition for which many veterans need ongoing integrated and well-coordinated care.”

The Veterans Health Administration (VHA) has 5 polytrauma rehabilitation centers, 23 polytrauma network sites, numerous polytrauma support clinics, and > 110 TBI teams. Rachel McArdle, deputy executive director of rehabilitation and prosthetic services at VHA, told the subcommittee that since 2007, VHA has screened 1.8 million veterans for TBI. Every veteran, she said, receives an individualized plan addressing physical, cognitive, and emotional needs, often integrated with mental health services and patient-centered care approaches.

Graham and others expressed concern that despite their importance, the CoEs faced daunting challenges.

“Budgets have generally increased in recent years, but often unpredictably,” Graham noted. “Due to the recent focus on downsizing VHA staffing, a number of key positions are currently vacant due to clinical and administrative staff reassignment, resignation to accept positions outside VHA, or opting for early or standard retirement.”

In a statement, Natalia S. Rost, MD, MPH, President of the American Academy of Neurology, urged Congress to continue to provide funds for Neurology CoEs: “We look forward to continuing to work with Congress to secure robust, sustained funding to ensure our nation’s veterans receive the highest quality of neurologic care for years to come.”

Joel Scholten, MD, VA Executive Director of Physical Medicine and Rehabilitation, told the panel that the VA Office of Research and Development allocated $50 million for fiscal year 2025 research projects on TBI. Some are aimed at developing better biomarkers not only for TBI but also co-occurring mental health diagnoses. “As we work to better understand and better identify biomarkers not only for TBI but also looking at those associated or affiliated risk factors that can enhance suicide risk, we'll better be able to care for veterans.”

“I’m confident that the VA has all the data, legal authority, and funding it needs to effectively treat TBI,” Rep. Mariannette Miller-Meeks (R-IA), subcommittee chair, added. “Here's where I’ve seen the VA needs improvement: Consistent quality in patient care and data.”

Still, Graham argued that staffing reductions may be straining VHA’s ability to continue its mission. Anxiety about job security, increased vacancies, inadequate space in overcrowded VA medical centers due to the return to office mandate, and the loss of psychological safety and a positive workplace culture threatened the quality of neurology care at VHA.

“The VHA has long promoted the path to becoming a high reliability organization, with an obsessive attention to accuracy and avoidance of clinical errors, in a climate of psychological safety that encourages reporting of mistakes and ‘near misses’ in a concerted effort to prevent patient harm,” he argued. “Unfortunately, these principles appear to be in abeyance at present.”

A study in veterans has found a link between dementia and severe chronic traumatic encephalopathy (CTE)—a degenerative brain disorder diagnosed after death that typically affects contact sports athletes and military personnel. Brain donors with advanced CTE (stage 4) were nearly 4.5 times more likely to have developed dementia than those without CTE. Individuals with stage 3 CTE had more than double the risk of dementia. The study was published in January in Alzheimer's and Dementia. 

CTE stages 1 and 2 were not associated with dementia, cognitive impairment, or functional decline. Researchers also did not observe mood or behavioral symptoms at any stage of the disease. Researchers from the Boston University CTE Center and Veterans Affairs Boston Healthcare System (VABHS) led the study, which was funded by grants from the National Institutes of Health (NIH).

“This study proves that CTE is not a benign brain disease and that it has a significant impact on people’s lives,” coauthor Ann C. McKee, MD, chief of neuropathology at VABHS and director of the Boston University CTE Center, told Federal Practitioner. 

McKee added that this research “provides evidence of a robust association between CTE and dementia, as well as cognitive symptoms, supporting our suspicions of CTE being a possible cause of dementia.”

Because CTE can only be diagnosed after death, researchers analyzed 614 donated brains from individuals with known exposure to repetitive head impacts. Among these donors, 366 (59.6%) had CTE and 248 (40.4%) did not. Most donors were male (97%), and most played American football (80.3%). Of the 614 donated brains, 20 (3.3%) were female. The average age of death from these 614 was 52 years, ranging from 13 to 98 years.

None of the donors had any of the 3 most common neurodegenerative causes of dementia: Alzheimer disease, dementia with Lewy bodies, or frontotemporal lobar degeneration.

Researchers also collected clinical information from individuals close to the donors. Typically, these are family members or close contacts through retrospective evaluations that combined online surveys, telephone interviews, and medical records. 

Data collected included demographics; educational attainment; athletic history (including sport, level of play, position, age at first exposure, and duration); military history; traumatic brain injury history; substance use; and medical, social, and family histories. 

CTE is often misdiagnosed as Alzheimer disease. In this study, among those diagnosed with dementia, 40% were informed they had Alzheimer, yet autopsy findings later showed no evidence of the disease. Another 38% were told the cause of dementia was unknown or could not be specified.

“In cases of dementia, when there is a history of repetitive head impacts from contact sports, military activities, or other exposures, CTE should be considered in the differential diagnosis,” McKee said. “Efforts should be made to distinguish CTE from Alzheimer disease and other causes of dementia during life.”

CTE shares features with Alzheimer, specifically the accumulation of abnormal tau protein. In healthy brains, tau helps maintain the stability and proper function of nerve cells. In CTE, however, tau accumulates in small clumps inside nerve cells that eventually form larger tangles.

Normally, the body clears excess tau protein, but in neurodegenerative diseases this process fails. The ensuing buildup damages brain cells, leading to cell death and the progressive symptoms of dementia.

Understanding how brain changes, including those related to CTE, relate to symptoms is of “paramount importance,” said Heather M. Snyder, PhD, senior vice president of medical and scientific relations at the Alzheimer’s Association in Chicago, who was not involved in the study.

Snyder described the research as “the first study to definitely demonstrate that brain changes caused by CTE are associated with the presence of dementia symptoms.” She also noted that the findings suggest a dose-response relationship, with more severe brain changes linked to worse cognitive symptoms.

The findings “open up new paths of research,” Snyder told Federal Practitioner, but also emphasized that improved tools are needed to detect these CTE-related brain changes in living individuals. 

“While we have made significant progress in understanding the diseases that cause dementia, we have much to learn,” Snyder said. “Continued and steadfast investment in research remains a priority to improve early detection during life and develop personalized approaches.”

Ann McKee reported that she is a member of the Mackey-White Committee of the National Football League Players Association and received funding from the National Institutes of Health, US Department of Veteran Affairs, the Buoniconti Foundation and the MacParkman Foundation during the conduct of the study. She reports honorarium for speaking engagements.

Heather Snyder is a full-time employee of the Alzheimer’s Association, Chicago, IL and has a spouse who is employed by Abbott in an unrelated area. She has no financial conflicts to disclose.

A study in veterans has found a link between dementia and severe chronic traumatic encephalopathy (CTE)—a degenerative brain disorder diagnosed after death that typically affects contact sports athletes and military personnel. Brain donors with advanced CTE (stage 4) were nearly 4.5 times more likely to have developed dementia than those without CTE. Individuals with stage 3 CTE had more than double the risk of dementia. The study was published in January in Alzheimer's and Dementia. 

CTE stages 1 and 2 were not associated with dementia, cognitive impairment, or functional decline. Researchers also did not observe mood or behavioral symptoms at any stage of the disease. Researchers from the Boston University CTE Center and Veterans Affairs Boston Healthcare System (VABHS) led the study, which was funded by grants from the National Institutes of Health (NIH).

“This study proves that CTE is not a benign brain disease and that it has a significant impact on people’s lives,” coauthor Ann C. McKee, MD, chief of neuropathology at VABHS and director of the Boston University CTE Center, told Federal Practitioner. 

McKee added that this research “provides evidence of a robust association between CTE and dementia, as well as cognitive symptoms, supporting our suspicions of CTE being a possible cause of dementia.”

Because CTE can only be diagnosed after death, researchers analyzed 614 donated brains from individuals with known exposure to repetitive head impacts. Among these donors, 366 (59.6%) had CTE and 248 (40.4%) did not. Most donors were male (97%), and most played American football (80.3%). Of the 614 donated brains, 20 (3.3%) were female. The average age of death from these 614 was 52 years, ranging from 13 to 98 years.

None of the donors had any of the 3 most common neurodegenerative causes of dementia: Alzheimer disease, dementia with Lewy bodies, or frontotemporal lobar degeneration.

Researchers also collected clinical information from individuals close to the donors. Typically, these are family members or close contacts through retrospective evaluations that combined online surveys, telephone interviews, and medical records. 

Data collected included demographics; educational attainment; athletic history (including sport, level of play, position, age at first exposure, and duration); military history; traumatic brain injury history; substance use; and medical, social, and family histories. 

CTE is often misdiagnosed as Alzheimer disease. In this study, among those diagnosed with dementia, 40% were informed they had Alzheimer, yet autopsy findings later showed no evidence of the disease. Another 38% were told the cause of dementia was unknown or could not be specified.

“In cases of dementia, when there is a history of repetitive head impacts from contact sports, military activities, or other exposures, CTE should be considered in the differential diagnosis,” McKee said. “Efforts should be made to distinguish CTE from Alzheimer disease and other causes of dementia during life.”

CTE shares features with Alzheimer, specifically the accumulation of abnormal tau protein. In healthy brains, tau helps maintain the stability and proper function of nerve cells. In CTE, however, tau accumulates in small clumps inside nerve cells that eventually form larger tangles.

Normally, the body clears excess tau protein, but in neurodegenerative diseases this process fails. The ensuing buildup damages brain cells, leading to cell death and the progressive symptoms of dementia.

Understanding how brain changes, including those related to CTE, relate to symptoms is of “paramount importance,” said Heather M. Snyder, PhD, senior vice president of medical and scientific relations at the Alzheimer’s Association in Chicago, who was not involved in the study.

Snyder described the research as “the first study to definitely demonstrate that brain changes caused by CTE are associated with the presence of dementia symptoms.” She also noted that the findings suggest a dose-response relationship, with more severe brain changes linked to worse cognitive symptoms.

The findings “open up new paths of research,” Snyder told Federal Practitioner, but also emphasized that improved tools are needed to detect these CTE-related brain changes in living individuals. 

“While we have made significant progress in understanding the diseases that cause dementia, we have much to learn,” Snyder said. “Continued and steadfast investment in research remains a priority to improve early detection during life and develop personalized approaches.”

Ann McKee reported that she is a member of the Mackey-White Committee of the National Football League Players Association and received funding from the National Institutes of Health, US Department of Veteran Affairs, the Buoniconti Foundation and the MacParkman Foundation during the conduct of the study. She reports honorarium for speaking engagements.

Heather Snyder is a full-time employee of the Alzheimer’s Association, Chicago, IL and has a spouse who is employed by Abbott in an unrelated area. She has no financial conflicts to disclose.

A study in veterans has found a link between dementia and severe chronic traumatic encephalopathy (CTE)—a degenerative brain disorder diagnosed after death that typically affects contact sports athletes and military personnel. Brain donors with advanced CTE (stage 4) were nearly 4.5 times more likely to have developed dementia than those without CTE. Individuals with stage 3 CTE had more than double the risk of dementia. The study was published in January in Alzheimer's and Dementia. 

CTE stages 1 and 2 were not associated with dementia, cognitive impairment, or functional decline. Researchers also did not observe mood or behavioral symptoms at any stage of the disease. Researchers from the Boston University CTE Center and Veterans Affairs Boston Healthcare System (VABHS) led the study, which was funded by grants from the National Institutes of Health (NIH).

“This study proves that CTE is not a benign brain disease and that it has a significant impact on people’s lives,” coauthor Ann C. McKee, MD, chief of neuropathology at VABHS and director of the Boston University CTE Center, told Federal Practitioner. 

McKee added that this research “provides evidence of a robust association between CTE and dementia, as well as cognitive symptoms, supporting our suspicions of CTE being a possible cause of dementia.”

Because CTE can only be diagnosed after death, researchers analyzed 614 donated brains from individuals with known exposure to repetitive head impacts. Among these donors, 366 (59.6%) had CTE and 248 (40.4%) did not. Most donors were male (97%), and most played American football (80.3%). Of the 614 donated brains, 20 (3.3%) were female. The average age of death from these 614 was 52 years, ranging from 13 to 98 years.

None of the donors had any of the 3 most common neurodegenerative causes of dementia: Alzheimer disease, dementia with Lewy bodies, or frontotemporal lobar degeneration.

Researchers also collected clinical information from individuals close to the donors. Typically, these are family members or close contacts through retrospective evaluations that combined online surveys, telephone interviews, and medical records. 

Data collected included demographics; educational attainment; athletic history (including sport, level of play, position, age at first exposure, and duration); military history; traumatic brain injury history; substance use; and medical, social, and family histories. 

CTE is often misdiagnosed as Alzheimer disease. In this study, among those diagnosed with dementia, 40% were informed they had Alzheimer, yet autopsy findings later showed no evidence of the disease. Another 38% were told the cause of dementia was unknown or could not be specified.

“In cases of dementia, when there is a history of repetitive head impacts from contact sports, military activities, or other exposures, CTE should be considered in the differential diagnosis,” McKee said. “Efforts should be made to distinguish CTE from Alzheimer disease and other causes of dementia during life.”

CTE shares features with Alzheimer, specifically the accumulation of abnormal tau protein. In healthy brains, tau helps maintain the stability and proper function of nerve cells. In CTE, however, tau accumulates in small clumps inside nerve cells that eventually form larger tangles.

Normally, the body clears excess tau protein, but in neurodegenerative diseases this process fails. The ensuing buildup damages brain cells, leading to cell death and the progressive symptoms of dementia.

Understanding how brain changes, including those related to CTE, relate to symptoms is of “paramount importance,” said Heather M. Snyder, PhD, senior vice president of medical and scientific relations at the Alzheimer’s Association in Chicago, who was not involved in the study.

Snyder described the research as “the first study to definitely demonstrate that brain changes caused by CTE are associated with the presence of dementia symptoms.” She also noted that the findings suggest a dose-response relationship, with more severe brain changes linked to worse cognitive symptoms.

The findings “open up new paths of research,” Snyder told Federal Practitioner, but also emphasized that improved tools are needed to detect these CTE-related brain changes in living individuals. 

“While we have made significant progress in understanding the diseases that cause dementia, we have much to learn,” Snyder said. “Continued and steadfast investment in research remains a priority to improve early detection during life and develop personalized approaches.”

Ann McKee reported that she is a member of the Mackey-White Committee of the National Football League Players Association and received funding from the National Institutes of Health, US Department of Veteran Affairs, the Buoniconti Foundation and the MacParkman Foundation during the conduct of the study. She reports honorarium for speaking engagements.

Heather Snyder is a full-time employee of the Alzheimer’s Association, Chicago, IL and has a spouse who is employed by Abbott in an unrelated area. She has no financial conflicts to disclose.

TOPLINE:

In patients with 5-20 brain metastases, stereotactic radiation improved symptoms and reduced interference with daily functioning compared to hippocampal-avoidance whole brain radiation. The weighted composite MD Anderson Symptom Inventory-Brain Tumor score changed from 2.69 to 2.37 with stereotactic radiation compared with 2.29 to 3.03 with hippocampal-avoidance whole brain radiation.

METHODOLOGY:

• Randomized trials have shown stereotactic radiation preserves neurocognitive function and patient-reported outcomes compared with whole brain radiation in patients with four or less brain metastases. For patients with more than four brain metastases, published randomized comparisons of stereotactic radiation vs whole brain radiation were lacking prior to this study.
• Researchers conducted a phase 3, open-label, randomized clinical trial at four US-based centers, enrolling 196 patients between April 2017 and May 2024, with final follow-up in March 2025.
• Participants included patients with 5-20 brain metastases and no prior brain-directed radiation, with a median of 14 brain metastases per patient and 25% having undergone prior neurosurgical resection.
• The primary outcome was the mean weighted patient-reported symptom severity and interference score change over 6 months. The researchers used the MD Anderson Symptom Inventory-Brain Tumor instrument, with scores ranging from 0-10 and change range of -10 to 10, to measure outcomes.
• Stereotactic radiation was delivered in either 1 day (20 Gy) or five daily fractions (30 Gy, or 25 Gy for surgically removed tumors), while hippocampal-avoidance whole brain radiation was administered as 30 Gy in 10 daily fractions with memantine.

TAKEAWAY:

• Primary outcome analysis showed that stereotactic radiation was linked to a change in the weighted composite MD Anderson Symptom Inventory-Brain Tumor score of 2.69 to 2.37 (mean change, -0.32) compared with 2.29 to 3.03 (mean change, 0.74) with hippocampal-avoidance whole brain radiation (mean difference, -1.06; 95% CI, -1.54 to -0.58; P < .001).
• Functional independence via the Barthel Index was better in the stereotactic radiation group at 4 months (mean difference, 6.79; 95% CI, 1.19-12.38; P = .02) and 12 months (mean difference, 7.92; 95% CI, 1.34-14.49; P = .02).
• New brain metastases were more frequent with stereotactic radiation (1-year cumulative incidence, 45.4% vs 24.2%; P = .003), while local recurrence was lower (3.2% vs 39.5%; P < .001).
• Grade 3-5 adverse events occurred in 12% of stereotactic radiation patients vs 13% in the hippocampal-avoidance whole brain radiation group, with fatigue being most common (28% vs 44%).

IN PRACTICE:

“While [the trial] clearly demonstrates that patients with 5-20 brain metastases have improved symptom burden and lowered interference with daily functioning, there are questions that remain for stereotactic radiosurgery in this population. Patients receiving stereotactic radiosurgery for brain metastases have a higher need for future salvage procedures, and this rate of salvage procedures is higher for patients with an increased number of brain metastases at diagnosis… Moreover, it has been shown that the upfront decision between stereotactic radiosurgery and whole brain radiotherapy is the single decision that contributes most to the cost of care of a patient with brain metastases,” said Michael Chan, MD, in an accompanying editorial published in JAMA.

SOURCE:

The study was led by Ayal A. Aizer, MD, MHS, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston. It was published online on February 19 in JAMA.

LIMITATIONS:

According to the authors, the study was not blinded, and the primary outcome was subjective. High mortality limited long-term data collection, reducing precision and biasing outcomes toward survivors. Additionally, randomization was not stratified by treating center, allowing possible unmeasured imbalances. The minimal clinically important difference had not been defined for many study outcome measures.

DISCLOSURES:

The trial was supported by Varian, a Siemens Healthineers Company. Aizer disclosed receiving grants from NH TherAguix Research outside the submitted work. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.

TOPLINE:

In patients with 5-20 brain metastases, stereotactic radiation improved symptoms and reduced interference with daily functioning compared to hippocampal-avoidance whole brain radiation. The weighted composite MD Anderson Symptom Inventory-Brain Tumor score changed from 2.69 to 2.37 with stereotactic radiation compared with 2.29 to 3.03 with hippocampal-avoidance whole brain radiation.

METHODOLOGY:

• Randomized trials have shown stereotactic radiation preserves neurocognitive function and patient-reported outcomes compared with whole brain radiation in patients with four or less brain metastases. For patients with more than four brain metastases, published randomized comparisons of stereotactic radiation vs whole brain radiation were lacking prior to this study.
• Researchers conducted a phase 3, open-label, randomized clinical trial at four US-based centers, enrolling 196 patients between April 2017 and May 2024, with final follow-up in March 2025.
• Participants included patients with 5-20 brain metastases and no prior brain-directed radiation, with a median of 14 brain metastases per patient and 25% having undergone prior neurosurgical resection.
• The primary outcome was the mean weighted patient-reported symptom severity and interference score change over 6 months. The researchers used the MD Anderson Symptom Inventory-Brain Tumor instrument, with scores ranging from 0-10 and change range of -10 to 10, to measure outcomes.
• Stereotactic radiation was delivered in either 1 day (20 Gy) or five daily fractions (30 Gy, or 25 Gy for surgically removed tumors), while hippocampal-avoidance whole brain radiation was administered as 30 Gy in 10 daily fractions with memantine.

TAKEAWAY:

• Primary outcome analysis showed that stereotactic radiation was linked to a change in the weighted composite MD Anderson Symptom Inventory-Brain Tumor score of 2.69 to 2.37 (mean change, -0.32) compared with 2.29 to 3.03 (mean change, 0.74) with hippocampal-avoidance whole brain radiation (mean difference, -1.06; 95% CI, -1.54 to -0.58; P < .001).
• Functional independence via the Barthel Index was better in the stereotactic radiation group at 4 months (mean difference, 6.79; 95% CI, 1.19-12.38; P = .02) and 12 months (mean difference, 7.92; 95% CI, 1.34-14.49; P = .02).
• New brain metastases were more frequent with stereotactic radiation (1-year cumulative incidence, 45.4% vs 24.2%; P = .003), while local recurrence was lower (3.2% vs 39.5%; P < .001).
• Grade 3-5 adverse events occurred in 12% of stereotactic radiation patients vs 13% in the hippocampal-avoidance whole brain radiation group, with fatigue being most common (28% vs 44%).

IN PRACTICE:

“While [the trial] clearly demonstrates that patients with 5-20 brain metastases have improved symptom burden and lowered interference with daily functioning, there are questions that remain for stereotactic radiosurgery in this population. Patients receiving stereotactic radiosurgery for brain metastases have a higher need for future salvage procedures, and this rate of salvage procedures is higher for patients with an increased number of brain metastases at diagnosis… Moreover, it has been shown that the upfront decision between stereotactic radiosurgery and whole brain radiotherapy is the single decision that contributes most to the cost of care of a patient with brain metastases,” said Michael Chan, MD, in an accompanying editorial published in JAMA.

SOURCE:

The study was led by Ayal A. Aizer, MD, MHS, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston. It was published online on February 19 in JAMA.

LIMITATIONS:

According to the authors, the study was not blinded, and the primary outcome was subjective. High mortality limited long-term data collection, reducing precision and biasing outcomes toward survivors. Additionally, randomization was not stratified by treating center, allowing possible unmeasured imbalances. The minimal clinically important difference had not been defined for many study outcome measures.

DISCLOSURES:

The trial was supported by Varian, a Siemens Healthineers Company. Aizer disclosed receiving grants from NH TherAguix Research outside the submitted work. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.

TOPLINE:

In patients with 5-20 brain metastases, stereotactic radiation improved symptoms and reduced interference with daily functioning compared to hippocampal-avoidance whole brain radiation. The weighted composite MD Anderson Symptom Inventory-Brain Tumor score changed from 2.69 to 2.37 with stereotactic radiation compared with 2.29 to 3.03 with hippocampal-avoidance whole brain radiation.

METHODOLOGY:

• Randomized trials have shown stereotactic radiation preserves neurocognitive function and patient-reported outcomes compared with whole brain radiation in patients with four or less brain metastases. For patients with more than four brain metastases, published randomized comparisons of stereotactic radiation vs whole brain radiation were lacking prior to this study.
• Researchers conducted a phase 3, open-label, randomized clinical trial at four US-based centers, enrolling 196 patients between April 2017 and May 2024, with final follow-up in March 2025.
• Participants included patients with 5-20 brain metastases and no prior brain-directed radiation, with a median of 14 brain metastases per patient and 25% having undergone prior neurosurgical resection.
• The primary outcome was the mean weighted patient-reported symptom severity and interference score change over 6 months. The researchers used the MD Anderson Symptom Inventory-Brain Tumor instrument, with scores ranging from 0-10 and change range of -10 to 10, to measure outcomes.
• Stereotactic radiation was delivered in either 1 day (20 Gy) or five daily fractions (30 Gy, or 25 Gy for surgically removed tumors), while hippocampal-avoidance whole brain radiation was administered as 30 Gy in 10 daily fractions with memantine.

TAKEAWAY:

• Primary outcome analysis showed that stereotactic radiation was linked to a change in the weighted composite MD Anderson Symptom Inventory-Brain Tumor score of 2.69 to 2.37 (mean change, -0.32) compared with 2.29 to 3.03 (mean change, 0.74) with hippocampal-avoidance whole brain radiation (mean difference, -1.06; 95% CI, -1.54 to -0.58; P < .001).
• Functional independence via the Barthel Index was better in the stereotactic radiation group at 4 months (mean difference, 6.79; 95% CI, 1.19-12.38; P = .02) and 12 months (mean difference, 7.92; 95% CI, 1.34-14.49; P = .02).
• New brain metastases were more frequent with stereotactic radiation (1-year cumulative incidence, 45.4% vs 24.2%; P = .003), while local recurrence was lower (3.2% vs 39.5%; P < .001).
• Grade 3-5 adverse events occurred in 12% of stereotactic radiation patients vs 13% in the hippocampal-avoidance whole brain radiation group, with fatigue being most common (28% vs 44%).

IN PRACTICE:

“While [the trial] clearly demonstrates that patients with 5-20 brain metastases have improved symptom burden and lowered interference with daily functioning, there are questions that remain for stereotactic radiosurgery in this population. Patients receiving stereotactic radiosurgery for brain metastases have a higher need for future salvage procedures, and this rate of salvage procedures is higher for patients with an increased number of brain metastases at diagnosis… Moreover, it has been shown that the upfront decision between stereotactic radiosurgery and whole brain radiotherapy is the single decision that contributes most to the cost of care of a patient with brain metastases,” said Michael Chan, MD, in an accompanying editorial published in JAMA.

SOURCE:

The study was led by Ayal A. Aizer, MD, MHS, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston. It was published online on February 19 in JAMA.

LIMITATIONS:

According to the authors, the study was not blinded, and the primary outcome was subjective. High mortality limited long-term data collection, reducing precision and biasing outcomes toward survivors. Additionally, randomization was not stratified by treating center, allowing possible unmeasured imbalances. The minimal clinically important difference had not been defined for many study outcome measures.

DISCLOSURES:

The trial was supported by Varian, a Siemens Healthineers Company. Aizer disclosed receiving grants from NH TherAguix Research outside the submitted work. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.