Clopidogrel hyper-response increases peripheral hemorrhagic complications without increasing intracranial complications in endovascular aneurysm treatments requiring dual antiplatelet therapy.

Clinical significance of increased clopidogrel response measured by VerifyNow P2Y12 assay is unclear; management guidelines are lacking in the context of neuroendovascular intervention. Our objective was to assess whether increased clopidogrel response predicts complications from endovascular aneurysm treatment requiring dual antiplatelet therapy. A single-institution, 9-year retrospective study of patients undergoing endovascular treatments for ruptured and unruptured aneurysms requiring aspirin and clopidogrel was conducted. Patients were grouped according to preoperative platelet inhibition in response to clopidogrel measured by the VerifyNow P2Y12 assay (VNP; P2Y12 reactivity units, PRU). Demographic and clinical features were compared across groups. Hemorrhagic complication rates (intracranial, major extracranial, minor extracranial) and thromboembolic complications (in-stent stenosis, stroke/transient ischemic attack) were compared, controlling for potential confounders and multiple comparisons. Data were collected from 284 patients across 317 procedures. Pre-operative VNP assays identified 9 % Extreme Responders (PRU ≤ 15), 13 % Hyper-Responders (PRU 16-60), 62 % Therapeutic Responders (PRU 61-214), 16 % Hypo-Responders (PRU ≥ 215). Increased response to clopidogrel was associated with increased risk of any hemorrhagic complication (≤60 PRU vs > 60 PRU; 39 % vs 24 %, P = 0.050); all intracranial hemorrhages occurred in patients with PRU > 60. Thromboembolic complications were similar between therapeutic and subtherapeutic patients (<215 PRU vs ≥ 215 PRU; 15 % vs 16 %, P = 0.835). Increased preoperative clopidogrel response is associated with increased rate of extracranial hemorrhagic complications in endovascular aneurysm treatments. Hyper-responders (16-60 PRU) and Extreme Responders (≤15 PRU) were not associated with intracranial hemorrhagic or thrombotic complications. Hypo-responders who underwent adjustment of antiplatelet therapy and neurointerventions did not experience higher rates of complications.

Clinical Utility of Routine Postprocedural Computed Tomography of the Head Following Elective Neuroendovascular Interventions.

BACKGROUND: Little evidence supports acquisition of routine head imaging after uncomplicated elective neurosurgical procedures for patients with unchanged neurological examinations; however, imaging is still performed by some neurointerventionalists. We assessed the clinical utility of routine computed tomography of the head (CTH) following elective neuroendovascular interventions, including aneurysm coiling, aneurysm stent-assisted coiling, aneurysm flow diversion, arteriovenous malformation/fistula embolization, middle meningeal artery embolization for subdural hematoma, extracranial carotid artery stenting, and venous sinus stenting. METHODS: Retrospective chart review identified patients undergoing neuroendovascular intervention from 2011 to 2021 at our institution. Demographic, clinical, and radiographic variables, including presenting signs and symptoms, antiplatelets and/or anticoagulant medications, intraprocedural complications, postprocedural CTH findings, and postprocedural neurological examinations, were recorded. Association of clinical variables with an abnormal postprocedural CTH was assessed with univariate analysis. Patients with ruptured vascular pathology, preoperative embolizations, and missing postprocedural CTH images and/or reports were excluded. RESULTS: Of 509 procedures identified, 354 were eligible for analysis; 4.8% of patients (17/354) had abnormal findings on postprocedural CTH. Nine patients had intraprocedural complications or new postprocedural neurological deficits that would have prompted imaging regardless of institutional practice. None of the remaining 8 (2.3%) patients required additional procedures. New postprocedural neurological deficit was the only significant predictor of abnormal postprocedural CTH (odds ratio = 6.79; 95% confidence interval, 2.01-20.32; P = 0.0009). CONCLUSIONS: In a large cohort of patients undergoing elective neuroendovascular intervention, no patients were identified for whom routine postprocedural CTH alone meaningfully altered their clinical care. Routine CTH is not necessary after uncomplicated elective neuroendovascular interventions performed with careful postprocedural neurological assessment.

Association of Chronic Kidney Disease With Risk of Intracerebral Hemorrhage.

Importance: The evidence linking chronic kidney disease (CKD) to spontaneous intracerebral hemorrhage (ICH) is inconclusive owing to possible confounding by comorbidities that frequently coexist in patients with these 2 diseases. Objective: To determine whether there is an association between CKD and ICH risk. Design, Setting, and Participants: A 3-stage study that combined observational and genetic analyses was conducted. First, the association between CKD and ICH risk was tested in the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study, a multicenter case-control study in the US. All participants with available data on CKD from ERICH were included. Second, this analysis was replicated in the UK Biobank (UKB), an ongoing population study in the UK. All participants in the UKB were included in this study. Third, mendelian randomization analyses were implemented in the UKB using 27 CKD-related genetic variants to test for genetic associations. ERICH was conducted from August 1, 2010, to August 1, 2017, and observed participants for 1 year. The UKB enrolled participants between 2006 and 2010 and will continue to observe them for 30 years. Data analysis was performed from November 11, 2019, to May 10, 2022. Exposures: CKD stages 1 to 5. Main Outcomes and Measures: The outcome of interest was ICH, ascertained in ERICH via expert review of neuroimages and in the UKB via a combination of self-reported data and International Statistical Classification of Diseases, Tenth Revision, codes. Results: In the ERICH study, a total of 2914 participants with ICH and 2954 controls who had available data on CKD were evaluated (mean [SD] age, 61.6 [14.0] years; 2433 female participants [41.5%]; 3435 male participants [58.5%]); CKD was found to be independently associated with higher risk of ICH (odds ratio [OR], 1.95; 95% CI, 1.35-2.89; P < .001). This association was not modified by race and ethnicity. Replication in the UKB with 1341 participants with ICH and 501 195 controls (mean [SD] age, 56.5 [8.1] years; 273 402 female participants [54.4%]; 229 134 male participants [45.6%]) confirmed this association (OR, 1.28; 95% CI, 1.01-1.62; P = .04). Mendelian randomization analyses indicated that genetically determined CKD was associated with ICH risk (OR, 1.56; 95% CI, 1.13-2.16; P = .007). Conclusions and Relevance: In this 3-stage study that combined observational and genetic analyses among study participants enrolled in 2 large observational studies with different characteristics and study designs, CKD was consistently associated with higher risk of ICH. Mendelian randomization analyses suggest that this association was causal. Further studies are needed to identify the specific biological pathways that mediate this association.

Nickels and tines: the myth of nickel allergy in intracranial stents.

BACKGROUND: Most intracranial stents contain nickel alloy, and nickel allergy or hypersensitivity is common. Neurological injury following endovascular treatment with a nickel containing intracranial stent has been reported in patients with purported nickel allergy, but it is unclear whether these reactions represent true nickel hypersensitivity. We quantified nickel release from commonly used intracranial stents to investigate whether such stents should be avoided in patients with nickel allergy. METHODS: We examined nickel release from seven commonly used intracranial stents: Enterprise, LVIS Jr, Neuroform, Wingspan, Zilver, Pipeline Flex Embolization Device, and Surpass Evolve. We incubated each stent in human plasma-like media for 30 days. Dimethylglyoxime (DMG) spot testing was performed on each stent to detect released nickel at 0 and 30 days. Inductively coupled plasma-optical emission spectroscopy (ICP-OES) was then used to quantify the nickel concentration of the media at 30 days. Nickel currency and nickel standard for atomic absorption spectrometry were used as positive controls. RESULTS: DMG spot tests indicated nickel release only from nickel currency at 0 and 30 days of incubation. No nickel release was detected from any stent at 30 days using ICP-OES. CONCLUSIONS: Nickel release from commonly used intracranial stents is negligible. These results suggest that previously reported hypersensitivity to these stents may be misattributed to nickel allergy, and that patients with nickel allergy may be safely treated with select nickel-containing stents.

Severe, Intolerable Fatigue Associated with Hyperresponse to Clopidogrel.

OBJECTIVE: Clopidogrel is a commonly used antiplatelet agent for the prevention of thromboembolic complications following neuroendovascular procedures, but anecdotal data have raised concern for the possibility that clopidogrel may induce severe, intolerable fatigue. The purpose of this study is to systematically investigate this phenomenon. METHODS: We performed a dual-institution, 9-year, retrospective study of patients undergoing clopidogrel therapy for neuroendovascular procedures. Patients were included only if their response to clopidogrel was assessed by platelet function testing using the VerifyNow P2Y12 (VNP) assay. Hyperresponse to clopidogrel was defined as P2Y12 reaction units ≤60. Patients were considered to have had clopidogrel-induced severe fatigue if the onset of symptoms followed the initiation of clopidogrel therapy; symptoms improved following a reduction in the dose of clopidogrel; and symptoms could not be attributed to any other medical explanation. RESULTS: Data were collected on 349 patients. Five patients (1.4%) met criteria for clopidogrel-induced severe fatigue. All 5 patients were female, ages 39-68. VNP assessments obtained while patients were symptomatic revealed hyperresponse to clopidogrel (0-22 P2Y12 reaction units). Symptoms improved in all 5 patients when the dose of clopidogrel was reduced by half. Notably, 30% of patients (n = 103) demonstrated a hyperresponse to clopidogrel on at least 1 VNP assessment, but 98 of these patients did not suffer from severe fatigue. CONCLUSIONS: A syndrome of severe fatigue and other constitutional symptoms is a rare but clinically significant side effect of hyperresponse to clopidogrel in patients undergoing neuroendovasular intervention.

Obstructive Sleep Apnea as a Risk Factor for Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: To determine whether obstructive sleep apnea (OSA) is associated with intracerebral hemorrhage (ICH) risk, we assessed premorbid OSA exposure of patients with nontraumatic ICH and matched controls. METHODS: Ethnic/Racial Variations of Intracerebral Hemorrhage is a multicenter, case-control study evaluating risk factors for ICH that recruited 3000 cases with ICH and 3000 controls. OSA status was ascertained using the Berlin Questionnaire as a surrogate for premorbid OSA. We performed logistic regression analyses to evaluate the association between OSA and ICH. RESULTS: Two thousand and sixty-four (71%) cases and 1516 (52%) controls were classified as having OSA by the Berlin Questionnaire. Cases with OSA were significantly more likely to be male and have hypertension, heart disease, hyperlipidemia, and higher body mass index compared with those without OSA. OSA was more common among cases compared with controls (71% versus 52%, odds ratio, 2.28 [95% CI, 2.05-2.55]). In a multivariable logistic regression model, OSA was associated with increased risk for ICH (odds ratio, 1.47 [95% CI, 1.29-1.67]). CONCLUSIONS: OSA is a risk factor for ICH.

Association of Serum IL-6 (Interleukin 6) With Functional Outcome After Intracerebral Hemorrhage.

BACKGROUND AND OBJECTIVES: IL-6 (interleukin 6) is a proinflammatory cytokine and an established biomarker in acute brain injury. We sought to determine whether admission IL-6 levels are associated with severity and functional outcome after spontaneous intracerebral hemorrhage (ICH). METHODS: We performed an exploratory analysis of the recombinant activated FAST trial (Factor VII for Acute ICH). Patients with admission serum IL-6 levels were included. Regression analyses were used to assess the associations between IL-6 and 90-day modified Rankin Scale. In secondary analyses, we used linear regression to evaluate the association between IL-6 and baseline ICH and perihematomal edema volumes. RESULTS: Of 841 enrolled patients, we included 552 (66%) with available admission IL-6 levels (mean age 64 [SD 13], female sex 203 [37%]). IL-6 was associated with poor outcome (modified Rankin Scale, 4-6; per additional 1 ng/L, odds ratio, 1.30 [95% CI, 1.04-1.63]; P=0.02) after adjustment for known predictors of outcome after ICH and treatment group. IL-6 was associated with ICH volume after adjustment for age, sex, and ICH location, and this association was modified by location (multivariable interaction, P=0.002), with a stronger association seen in lobar (ß, 12.51 [95% CI, 6.47-18.55], P<0.001) versus nonlobar (ß 5.32 [95% CI, 3.36-7.28], P<0.001) location. IL-6 was associated with perihematomal edema volume after adjustment for age, sex, ICH volume, and ICH location (ß 1.22 [95% CI, 0.15-2.29], P=0.03). Treatment group was not associated with IL-6 levels or outcome. CONCLUSIONS: In the FAST trial population, higher admission IL-6 levels were associated with worse 90-day functional outcome and larger ICH and perihematomal edema volumes.

Time-dynamic pulse modulation of spinal cord stimulation reduces mechanical hypersensitivity and spontaneous pain in rats.

Enhancing the efficacy of spinal cord stimulation (SCS) is needed to alleviate the burden of chronic pain and dependence on opioids. Present SCS therapies are characterized by the delivery of constant stimulation in the form of trains of tonic pulses (TPs). We tested the hypothesis that modulated SCS using novel time-dynamic pulses (TDPs) leads to improved analgesia and compared the effects of SCS using conventional TPs and a collection of TDPs in a rat model of neuropathic pain according to a longitudinal, double-blind, and crossover design. We tested the effects of the following SCS patterns on paw withdrawal threshold and resting state EEG theta power as a biomarker of spontaneous pain: Tonic (conventional), amplitude modulation, pulse width modulation, sinusoidal rate modulation, and stochastic rate modulation. Results demonstrated that under the parameter settings tested in this study, all tested patterns except pulse width modulation, significantly reversed mechanical hypersensitivity, with stochastic rate modulation achieving the highest efficacy, followed by the sinusoidal rate modulation. The anti-nociceptive effects of sinusoidal rate modulation on EEG outlasted SCS duration on the behavioral and EEG levels. These results suggest that TDP modulation may improve clinical outcomes by reducing pain intensity and possibly improving the sensory experience.

Automated and rapid self-report of nociception in transgenic mice.

There are currently no rapid, operant pain behaviors in rodents that use a self-report to directly engage higher-order brain circuitry. We have developed a pain detection assay consisting of a lick behavior in response to optogenetic activation of predominantly nociceptive peripheral afferent nerve fibers in head-restrained transgenic mice expressing ChR2 in TRPV1 containing neurons. TRPV1-ChR2-EYFP mice (n = 5) were trained to provide lick reports to the detection of light-evoked nociceptive stimulation to the hind paw. Using simultaneous video recording, we demonstrate that the learned lick behavior may prove more pertinent in investigating brain driven pain processes than the reflex behavior. Within sessions, the response bias of transgenic mice changed with respect to lick behavior but not reflex behavior. Furthermore, response similarity between the lick and reflex behaviors diverged near perceptual threshold. Our nociceptive lick-report detection assay will enable a host of investigations into the millisecond, single cell, neural dynamics underlying pain processing in the central nervous system of awake behaving animals.