Sex differences in patients with and without high-risk factors associated with aneurysmal subarachnoid hemorrhage.

BACKGROUND: Controversy remains regarding the appropriate screening for intracranial aneurysms or for the treatment of aneurysmal subarachnoid hemorrhage (aSAH) for patients without known high-risk factors for rupture. This study aimed to assess how sex affects both aSAH presentation and outcomes for aSAH treatment. METHOD: A retrospective cohort study was conducted of all patients treated at a single institution for an aSAH during a 12-year period (August 1, 2007-July 31, 2019). An analysis of women with and without high-risk factors was performed, including a propensity adjustment for a poor neurologic outcome (modified Rankin Scale [mRS] score > 2) at follow-up. RESULTS: Data from 1014 patients were analyzed (69% [n = 703] women). Women were significantly older than men (mean ± SD, 56.6 ± 14.1 years vs 53.4 ± 14.2 years, p < 0.001). A significantly lower percentage of women than men had a history of tobacco use (36.6% [n = 257] vs 46% [n = 143], p = 0.005). A significantly higher percentage of women than men had no high-risk factors for aSAH (10% [n = 70] vs 5% [n = 16], p = 0.01). The percentage of women with an mRS score > 2 at the last follow-up was significantly lower among those without high-risk factors (34%, 24/70) versus those with high-risk factors (53%, 334/633) (p = 0.004). Subsequent propensity-adjusted analysis (adjusted for age, Hunt and Hess grade, and Fisher grade) found no statistically significant difference in the odds of a poor outcome for women with or without high-risk factors for aSAH (OR = 0.7, 95% CI = 0.4-1.2, p = 0.18). CONCLUSIONS: A higher percentage of women versus men with aSAH had no known high-risk factors for rupture, supporting more aggressive screening and management of women with unruptured aneurysms.

A Review of Preoperative Embolization Effectiveness in Patients With Arteriovenous Malformations.

BACKGROUND AND OBJECTIVES: Preoperative embolization of arteriovenous malformations (AVMs) remains controversial. This study sought to analyze the cost-effectiveness of preoperative embolization of AVMs. METHODS: Patients who underwent AVM resection at a single institute (January 1, 2015-December 31, 2020) were analyzed. Patients with preoperative embolization (embolization cohort) were compared with those without preoperative embolization (nonembolization cohort). Cost-effectiveness score (CE) was the primary outcome of interest and was determined by dividing the total 1-year cost by effectiveness, which was derived from a validated preoperative to last follow-up change in the modified Rankin Scale utility score. A lower CE signifies a more cost-effective treatment strategy. RESULTS: Of 188 patients, 88 (47%) underwent preoperative embolization. The mean (SD) total cost was higher in the embolization group than in the nonembolization group ($117 594 [$102 295] vs $84 348 [$82 326]; P < .001). The mean (SD) CE was higher in the embolization cohort ($336 476 [$1 303 842]) than in the nonembolization cohort ($100 237 [$246 255]; P < .001). Among patients with Spetzler-Martin (SM) grade I and II AVMs, the mean (SD) CE was higher in the embolization (n = 40) than in the nonembolization (n = 72) cohort ($164 950 [$348 286] vs $69 021 [$114 938]; P = .004). Among patients with SM grade III AVMs, the mean (SD) CE was lower in the embolization (n = 33) than in the nonembolization (n = 25) cohort ($151 577 [$219 130] vs $189 195 [$446 335]; P = .006). The mean (SD) CE was not significantly different between cohorts among patients with higher-grade AVMs (embolization cohort [n = 3] vs nonembolization cohort [n = 15]: $503 639 [$776 492] vs $2 048 419 [$4 794 758]; P = .49). The mean CE for embolized SM grade III aneurysms was nonsignificant in the ruptured group; however, for the unruptured group, CE was significantly higher in the embolization cohort (n = 26; $160 871 [$240 535]) relative to the nonembolization cohort (n = 15; $108 152 [$166 446]) ( P = .006). CONCLUSION: Preoperative embolization was cost-effective for patients with SM grade III AVMs but not for patients with lower-grade AVMs.

Early Treatment of Ruptured Cerebral Arteriovenous Malformations: Analysis of Neurological Outcomes and Health Care Costs.

BACKGROUND: The timing of surgical resection is controversial when managing ruptured arteriovenous malformations (AVMs) and varies considerably among centers. OBJECTIVE: To retrospectively analyze clinical outcomes and hospital costs associated with delayed treatment in a ruptured cerebral AVM patient cohort. METHODS: Patients undergoing surgical treatment for a ruptured cerebral AVM (January 1, 2015-December 31, 2020) were retrospectively analyzed. Patients who underwent emergent treatment of a ruptured AVM because of acute herniation were excluded, as were those treated >180 days after rupture. Patients were stratified by the timing of surgical intervention relative to AVM rupture into early (postbleed days 1-20) and delayed (postbleed days 21-180) treatment cohorts. RESULTS: Eighty-seven patients were identified. The early treatment cohort comprised 75 (86%) patients. The mean (SD) length of time between AVM rupture and surgical resection was 5 (5) days in the early cohort and 73 (60) days in the delayed cohort ( P < .001). The cohorts did not differ with respect to patient demographics, AVM size, Spetzler-Martin grade, frequency of preoperative embolization, or severity of clinical presentation ( P ≥ .15). Follow-up neurological status was equivalent between the cohorts ( P = .65). The associated mean health care costs were higher in the delayed treatment cohort ($241 597 [$99 363]) than in the early treatment cohort ($133 989 [$110 947]) ( P = .02). After adjustment for length of stay, each day of delayed treatment increased cost by a mean of $2465 (95% CI = $967-$3964, P = .002). CONCLUSION: Early treatment of ruptured AVMs was associated with significantly lower health care costs than delayed treatment, but surgical and neurological outcomes were equivalent.

Occipital Artery to Middle Cerebral Artery Direct Bypass: A Salvage Revascularization Technique for Ischemic Moyamoya Disease.

OBJECTIVE: The main treatment for moyamoya disease (MMD) is revascularization surgery. Most bypasses use the superficial temporal artery (STA) as the donor vessel. However, even if the STA-middle cerebral artery (MCA) bypass is functioning, the affected hemisphere can continue to be symptomatically malperfused. We sought to assess the efficacy of salvage direct revascularization surgery using the occipital artery (OA) as a donor vessel in patients with ischemic MMD who experience continued cerebral malperfusion despite previous successful STA-MCA bypass. METHODS: We retrospectively analyzed the cerebrovascular databases of 2 surgeons and described patients in whom the OA was used as the donor vessel for direct revascularization. RESULTS: Seven patients were included (5 women). Previous STA-MCA bypasses were direct (n = 2), indirect (n = 3), or combined/multiple (n = 2). The mean (SD) interval between STA-MCA and OA-MCA procedures was 29.2 (13.1) months. Despite an intact STA-MCA bypass in all 7 cases, all 7 patients had recurrent symptoms and demonstrated residual impaired cerebral perfusion. All 7 patients underwent successful OA-MCA direct revascularization. Follow-up perfusion imaging was obtained for 6 of 7 patients. All 6 of these patients demonstrated improved cerebral blood flow to the revascularized hemispheres. All 7 patients demonstrated clinical improvement. CONCLUSIONS: Patients with ischemic MMD who have continued symptoms and cerebral malperfusion despite previous successful STA-MCA bypass present a challenging clinical scenario. Our series highlights the potential utility of the OA-MCA direct bypass as a salvage therapy for these patients.

Retained radial catheters associated with variant radial anatomy in neurointerventional procedures.

BACKGROUND: Transradial artery access (TRA) for neurointerventional procedures is gaining widespread acceptance. However, complications that were previously rare may arise as TRA procedures increase. Here we report a series of retained catheter cases with a literature review. METHODS: All patients who underwent a neurointerventional procedure during a 23-month period at a single institution were retrospectively reviewed for a retained catheter in TRA cases. In cases of retained catheters, imaging was reviewed for anatomical variances in the radial artery, and clinical and demographic case details were analyzed. RESULTS: A total of 1386 nondiagnostic neurointerventional procedures were performed during the study period, 631 (46%) initially via TRA. The 631 TRA cases were performed for aneurysm embolization (n=221, 35%), mechanical thrombectomy (n=116, 18%), carotid stent/angioplasty (n=40, 6%), arteriovenous malformation embolization (n=38, 6%), and other reasons (n=216, 34%). Thirty-nine (6%) TRA procedures crossed over to femoral access, most commonly because the artery of interest could not be catheterized (26/39, 67%). A retained catheter was identified in five cases (1%), and one (0.2%) patient had an entrapped catheter that was recovered. All six patients with a retained or entrapped catheter had aberrant radial anatomy. CONCLUSION: Retained catheters for neurointerventional procedures performed via TRA are rare. However, this complication may be associated with variant radial anatomy. With the increased use of TRA for neurointerventional procedures, awareness of anatomical abnormalities that may lead to a retained catheter is necessary. We propose a simple protocol to avoid catheter entrapment, including in emergent situations such as TRA for stroke thrombectomy.

Assessing the volume-outcome relationship of carotid artery stenting in nationwide administrative data: a challenge of patient population bias.

BACKGROUND: Studies have shown an association between surgical treatment volume and improved quality metrics. This study evaluated nationwide results in carotid artery stenting (CAS) procedural readmission rates, costs, and length of stay based on hospital treatment volume. METHODS: We used the Nationwide Readmissions Database for carotid stenosis from 2010 to 2015. Patients receiving CAS were matched based on demographics, illness severity, and relevant comorbidities. Patients were matched 1:1 between low- and high-volume centers using a non-parametric preprocessing matching program to adjust for parametric causal inferences. Nearest-neighbor propensity score matching was performed using logit distance. RESULTS: Low- and high-volume centers admitted a mean (SD) of 4.68 (3.79) and 25.10 (16.86) patients undergoing CAS per hospital, respectively. Comorbidities were significantly different and initially could not be adequately matched. Because of significant differences in baseline patient population characteristics after attempted matching between low- and high-volume centers, we used propensity adjustment with multivariate analysis. Using this alternative approach, no significant differences were observed between low- and high-volume centers for the presence of any complication, postoperative stroke, postoperative myocardial infarction, and readmission at 30 days. CONCLUSION: In 1:1 nearest-neighbor matching with a high number of patients, our analysis did not result in well-matched cohorts for the effect of case volume on outcomes. Comparing analytical techniques for various outcomes highlights that outcome disparities may not be related to quality differences based on hospital size, but rather variability in patient populations between low- and high-volume institutions.

Incidence and Prediction of Chronic Depression Following Aneurysmal Subarachnoid Hemorrhage: A Single-Center 17-Year Experience.

OBJECTIVE: The incidence and risk factors for chronic depression after aneurysmal subarachnoid hemorrhage (aSAH) are described. METHODS: Patients with aSAH treated at a single institution (January 1, 2003-December 31, 2019) and a modified Rankin Scale score ≤3 at follow-up who were evaluated for chronic depression were analyzed. Chronic depression was defined using a depression screening questionnaire as ≥5 positive answers for symptoms lasting >2 weeks. A predictive model was designed for the primary outcome of depression. RESULTS: Among 1419 patients with aSAH, 460 patients were analyzed; 130 (28%) had major depressive disorder. Mean follow-up was >6 years. Higher depression rates were associated with tobacco smoking (odds ratio [OR] = 2.64, P < 0.001), illicit drug use (OR = 2.35, P = 0.007), alcohol use disorder (1.92, P = 0.04), chronic obstructive pulmonary disease (COPD) (OR=2.68, P = 0.03), and vasospasm requiring angioplasty (OR=2.09, P = 0.048). The predictive model included tobacco smoking, illicit drug use, liver disease, COPD, diabetes, nonsaccular aneurysm type, anterior communicating artery or anterior cerebral artery aneurysm location, refractory spasm requiring angioplasty, and a modified Rankin Scale score at discharge of >1 (P ≤ 0.03). The model performed with appropriate goodness of fit and an area under the receiver operator curve of 0.70 for depression. Individual independent predictors of depression were tobacco smoking, COPD, diabetes, and nonsaccular aneurysm. CONCLUSIONS: A substantial percentage of patients had symptoms of depression on follow-up. The proposed predictive model for depression may be a useful clinical tool to identify patients at high risk for developing depression who warrant early screening and evaluation.

Relationship between cerebral vasospasm vascular territory and functional outcome after aneurysmal subarachnoid hemorrhage.

BACKGROUND: Vasospasm following aneurysmal subarachnoid hemorrhage (SAH) contributes significant morbidity and mortality after brain aneurysm rupture. However, the association between vascular territory of vasospasm and clinical outcome has not been studied. We present a hypothesis-generating study to determine whether the location of vasospasm within the intracranial circulation is associated with functional outcome after SAH. METHODS: A retrospective analysis of a prospective, intention-to-treat trial for aneurysmal SAH was performed to supplement trial outcomes with in-hospital angiographic imaging and treatment variables regarding vasospasm. The location of vasospasm and the position on the vessel (distal vs proximal) were evaluated. Modified Rankin scale (mRS) outcomes were assessed at discharge and 6 months, and predictive models were constructed. RESULTS: A total of 406 patients were included, 341 with follow-up data at 6 months. At discharge, left-sided vasospasm was associated with poor outcome (odds ratio (OR), 2.37; 95% CI, 1.25 to 4.66; P=0.01). At 6 months, anterior cerebral artery (ACA) vasospasm (OR, 3.87; 95% CI, 1.29 to 11.88; P=0.02) and basilar artery (BA) vasospasm (OR, 6.22; 95% CI, 1.54 to 27.11; P=0.01) were associated with poor outcome after adjustment. A model predicting 6-month mRS score and incorporating vasospasm variables achieved an area under the curve of 0.85 and a net improvement in reclassification of 13.2% (P<0.01) compared with a previously validated predictive model for aneurysmal SAH. CONCLUSIONS: In aneurysmal SAH, left-sided vasospasm is associated with worse discharge functional status. At 6 months, both ACA and BA vasospasm are associated with unfavorable functional status.

Direct puncture of the superior ophthalmic vein for carotid cavernous fistulas: a 21-year experience.

BACKGROUND: Direct puncture of the superior ophthalmic vein (SOV) is an alternative approach to traversing the inferior petrosal sinus for embolization of carotid cavernous fistulas (CCFs). OBJECTIVE: To analyze direct SOV puncture for the treatment of CCFs and review the literature. METHODS: All patients at a single center, treated for a CCF with direct SOV cannulation between January 1, 2000, and December 31, 2020, were retrospectively analyzed. An additional review of the literature for all case series for direct puncture of the SOV for treatment of CCF was performed. RESULTS: During the 21-year study period, direct cannulation of the SOV for treatment of a CCF was attempted for 19 patients, with the procedure aborted for one patient because of an inability to navigate the wire into the distal aspect of the cavernous sinus. In 18 patients with direct SOV CCF treatment, 1 experienced a minor complication with an asymptomatic postoperative hemorrhage. Angiographic cure and improvement of symptoms were achieved in 17 patients with a mean (SD) follow-up of 6 (5.2) months. In the review of the literature, an additional 45 patients were reported to have direct cannulation of the SOV for CCF treatment, with angiographic cure in 43 (96%) and decreased objective visual acuity in 1 (2%). CONCLUSION: Direct SOV cannulation to treat CCFs is safe and effective. Although it is typically used after other endovascular approaches have failed, SOV access for CCF treatment may be warranted as a first-line treatment for select patients.

Nationwide Readmission Rates and Hospital Charges for Patients With Surgical Evacuation of Nontraumatic Subdural Hematomas: Part 1-Craniotomy.

BACKGROUND: Despite patients experiencing high recurrence and readmission rates after surgical management of nontraumatic subdural hematomas (SDHs), few studies have examined the causes and predictors of unplanned readmissions in this population on a national scale. OBJECTIVE: To analyze independent factors predicting 30-day hospital readmissions after surgical treatment of nontraumatic SDH in patients who survived their index surgery and evaluate hospital readmission rates and charges. METHODS: Using the Nationwide Readmissions Database, we identified patients who underwent craniotomy for nontraumatic SDH evacuation (2010-2015) using a retrospective cohort observational study design. National estimates and variances within the cohort were calculated after stratifying, hospital clustering, and weighting variables. RESULTS: Among 49 013 patients, 10 643 (21.7%) had at least 1 readmission within 30 days of their index treatment and 38 370 (78.3%) were not readmitted. Annual readmission rates did not change during the study period ( P = .74). The most common primary causes of 30-day readmissions were recurrent SDH (n = 3949, 37.1%), venous thromboembolism (n = 1373, 12.9%), and delayed hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (n = 1363, 12.8%). Comorbidities that independently predicted readmission included congestive heart failure, chronic obstructive pulmonary disease, coagulopathy, diabetes mellitus, liver disease, lymphoma, fluid and electrolyte disorders, metastatic cancer, peripheral vascular disease, psychosis, and renal failure ( P ≤ .03). Household income in the 51st to 75th percentile was associated with a decreased risk of readmission. CONCLUSION: National trends in 30-day readmission rates after nontraumatic SDH treatment by craniotomy provide quality benchmarks that can be used to drive quality improvement efforts on a national level.

Clinical Trials of Microsurgery for Cerebral Aneurysms: Past and Future.

BACKGROUND: New findings and research regarding the microsurgical treatment of intracerebral aneurysms (IAs) continue to advance even in the era of endovascular therapies. Research in the past 2 decades has continued to revolve around the question of whether open surgery or endovascular treatment is preferable. The answer remains both complex and in flux. OBJECTIVE: This review focuses on microsurgery, reflects on the research decisions of previous landmark studies, and proposes future study designs that may further our understanding of IAs and how best to treat them. RESULTS: The future of IA research may include a combination of pragmatic trials, artificial intelligence integrated tools, and mining of large data sets, in addition to the publication of high-quality single-center studies. CONCLUSIONS: The future will likely emphasize testing innovative techniques, looking at granular patient data, and considering every patient encounter as a potential source of knowledge, creating a system in which data are updated daily because each patient interaction contributes to answering important research questions.

Effects of Preoperative Embolization on Spetzler-Martin Grade I and II Arteriovenous Malformations: A Propensity-Adjusted Analysis.

BACKGROUND: Cerebral arteriovenous malformations (AVMs) with low Spetzler-Martin grades (I and II) are associated with good neurological outcomes after microsurgical resection; however, the use of preoperative embolization for these lesions is controversial. OBJECTIVE: To compare the neurological outcomes of preoperative embolization with no embolization in patients with low-grade AVMs. METHODS: Patients with a Spetzler-Martin grade I or II AVM who underwent microsurgical resection during January 1, 1997, through December 31, 2019, were analyzed. Patients undergoing preoperative embolization were compared with patients not undergoing embolization. A propensity score was constructed from baseline characteristics and used to match intervention (embolization) and control (nonembolization) groups in a 1:1 ratio. The primary outcome was poor neurological status on last follow-up examination, defined as a modified Rankin Scale score >2 and a modified Rankin Scale score worse at follow-up than at the preoperative examination. RESULTS: Of the 603 patients analyzed, 310 (51.4%) underwent preoperative embolization and 293 (48.6%) did not. Patients in the embolization cohort compared with those in the nonembolization cohort had a higher percentage of Spetzler-Martin grade II AVMs (71.6% vs 52.6%, P < .001) and a lower percentage of hemorrhage (41% vs 55%, P = .001). After propensity score matching, no differences were found between paired cohorts (each N = 203) for baseline characteristics with a significant reduction in absolute standardized mean differences. No significant differences were found in primary outcomes between treatment groups in the matched or unmatched cohorts. CONCLUSION: Preoperative embolization of low-grade Spetzler-Martin AVMs is not associated with improved neurological outcomes after microsurgical resection.

In Vivo Preclinical Quantitative Flow Analysis of Arterial Anastomosis Using a Microvascular Anastomotic Coupler and Clinical Application for Extracranial-to-Intracranial Bypass.

OBJECTIVE: Although several commercially available sutureless anastomotic techniques are available, they are not routinely used in neurosurgery. We performed an in vivo flow analysis of end-to-end anastomosis using a microvascular coupler device in rats. We report our first clinical use of the microvascular anastomotic coupler. METHODS: Bilateral rat common carotid arteries (CCAs) were exposed, and a microvascular coupler was used to perform 8 anastomoses. A microflow probe provided quantitative measurement of blood-flow volume. Flow augmentation was assessed with end-to-side anastomoses connecting the distal CCA to the jugular vein (JV). A patient with chronic dominant hemisphere atherosclerotic ischemic disease and progressive symptoms refractory to medical management underwent end-to-end cerebral artery bypass using the microvascular coupler. RESULTS: Mean preanastomosis flow in the rat CCA was 3.95 ± 0.45 mL/min; this flow was maintained at 3.99 ± 0.24 mL/min on final measurements 54-96 minutes postanastomosis. Total occlusion time for each rat CCA was 12-19 minutes. After end-to-side anastomosis, with proximal and distal JV patent, CCA flow increased 477% to 22.8 ± 3.70 mL/min (P = 0.04, proximal; P = 0.01, distal). After in vivo testing, we successfully used the coupler clinically in a superficial temporal artery-to-middle cerebral artery bypass for dominant hemisphere flow augmentation. CONCLUSIONS: In vivo quantitative flow analysis demonstrated no flow difference between an unaltered artery and artery with end-to-end anastomosis using a microvascular coupler in rats. A 1-mm coupled anastomosis achieved a 4-fold flow increase with low-resistance venous outflow in rats, simulating increased arterial demand. The coupler was successfully used for extracranial-to-intracranial bypass in a patient.

Radiographic clearance of chronic subdural hematomas after middle meningeal artery embolization.

BACKGROUND: Few reports discuss variables associated with improved outcomes after middle meningeal artery (MMA) embolization for chronic subdural hematomas (cSDHs). We analyzed radiographic evidence of cSDH clearance after MMA embolization to elucidate optimal techniques, hematoma clearance rates, and suitable length of follow-up. METHODS: Patients who underwent MMA embolization for cSDH from January 1, 2018 through December 31, 2020 were analyzed. Patient characteristics, demographics, and technical procedural details were examined. Outcomes for cSDHs analyzed included complete or near-complete resolution at 30, 90, and 180 days following embolization. A multivariable logistic regression analysis identified variables predictive of rapid clearance and resolution of hematomas at 90 days. RESULTS: The study cohort comprised 66 patients with 84 treated cSDHs. The mean (SD) cSDH size differed significantly at 30-day (8.8 (4.3) mm), 90-day (3.4 (3.0) mm), and 180-day (1.0 (1.7) mm) follow-up (p<0.001). More cSDHs had complete or near-complete resolution at 180 days (92%, 67/73) than at 90 (63%, 45/72) and 30 days (18%, 15/84) post-embolization (p<0.001). Only distal embolysate penetration was independently associated with rapid clearance (OR 3.9, 95% CI 1.4 to 11.1; p=0.01) and resolution of cSDHs at 90 days (OR 5.0, 95% CI 1.7 to 14.6; p=0.003). CONCLUSION: Although 63% of cSDHs with MMA embolization had complete or near-complete resolution by 90 days post-procedure, 92% reached this stage by 180 days. Therefore, 90-day follow-up may be insufficient to determine the effectiveness of MMA embolization for cSDHs, particularly compared with surgical evacuation alone. Also, distal MMA penetration may be associated with more rapid hematoma clearance.

Chronic headaches and middle meningeal artery embolization.

BACKGROUND: The middle meningeal artery (MMA) has been implicated in chronic headaches, but no studies have examined the relationship between MMA embolization and headaches. METHODS: Patients treated with MMA embolization for a chronic subdural hematoma (cSDH) between January 1, 2018, and December 31, 2020, were retrospectively assessed. Patients with a Glasgow Coma Scale (GCS) score of 15 at discharge received a follow-up telephone call to assess their history of chronic headache, defined as a headache ≥2 years before the cSDH and symptoms ≥2 days/month. A Headache Impact Test (HIT-6) was performed during the follow-up telephone call. The primary outcome was resolution or improvement of headaches after embolization. RESULTS: Of 76 patients undergoing MMA embolization for a cSDH during the study period, 56 (74%) had a discharge GCS score of 15. Of these 56 patients, 46 (82%) responded to a follow-up telephone call and were analyzed (mean [SD] age 68 [11] years; 36 [78%] men and 10 [22%] women). Nine (20%) reported chronic headaches before embolization. With a mean (SD) follow-up of 489 (173) days, eight of the nine patients reported improvement of chronic headaches, with seven having complete resolution. For these nine patients, the mean (SD) HIT-6 score was significantly higher before embolization than after embolization (64 [7.1] vs 40 [9.1], p<0.001). CONCLUSION: In patients with chronic headaches who underwent MMA embolization for a cSDH, the majority reported improvement of headaches after the procedure. Future prospective studies are warranted to assess the usefulness of MMA embolization to treat chronic headaches.