Spinal Nerve Root Stimulation for Chronic Pain: A Systematic Review.

OBJECTIVE: Spinal cord stimulation (SCS) has been used as a minimally invasive and effective treatment modality for various chronic pain disorders, with the main target being stimulation of the dorsal columns; however, certain neuropathic pain areas involve dermatomes that are suboptimally covered by SCS. Stimulation of the spinal nerve roots has the advantage of targeting one or several dermatomes at the same time. The aim of this systematic review is to investigate the efficacy of spinal nerve root stimulation (SNRS) for chronic pain disorders. MATERIALS AND METHODS: A detailed literature review was performed through the Ovid Embase and MEDLINE data bases in addition to reference searching. Gray literature was included by searching through common search engines using a simplified search strategy. Studies included were focused on adult patients (aged >18 years), diagnosis of chronic pain syndrome (including but not limited to complex regional pain syndrome, persistent spinal pain syndrome, neuropathic pain secondary to trauma or infection, postherpetic pain, and cancer pain). Patients must have undergone SNRS insertion, with ≥six months of documented pain intensity scores on follow-up. RESULTS: A total of 40 studies underwent full text review, and 13 articles were included in final analysis. Mean preoperative pain intensity was 8.14 ± 0.74 on the visual analog scale, whereas mean postoperative pain intensity at one year was 3.18 ± 1.44. Of 119 patients, 83 (70%) achieved ≥50% reduction in pain intensity after SNRS, whereas 36 (30%) achieved <50% reduction in pain intensity. Only three studies assessed changes in analgesia medication dose and reported morphine equivalent doses varied by case series. Overall, there was a trend toward a reduction in analgesia medications in the postoperative period. CONCLUSIONS: SNRS led to a mean 44% reduction in pain intensity, with a low level of certainty. In addition, there is some evidence to suggest that using SNRS is associated with reduced use of analgesics, including morphine and gabapentin.

Surgical Interventions Targeting the Nucleus Caudalis for Craniofacial Pain: A Systematic and Historical Review.

INTRODUCTION: Craniofacial pain is a prevalent group of conditions, and when refractory to conventional treatments, it poses a significant burden. The last decade has seen a renewed interest in the multimodal management of pain. Interventions targeting the nucleus caudalis (NC) of the trigeminocervical complex have been available as a treatment option since the 1930s, yet evidence for efficacy remains limited. MATERIALS AND METHODS: We present a systematic review of the literature providing a historical perspective on interventions targeting the NC leading up to the present. We examine the various intervention techniques, clinical indications, and procedural efficacy. A novel outcome-reporting scheme was devised to enable comparison among studies owing to historically variable reporting methods. RESULTS: A review of the literature revealed 33 retrospective studies published over the last 80 years, reporting on 827 patients. The most common technique was the open NC dorsal root entry zone nucleotomy/tractotomy; however, there has been an emergence of novel approaches such as endoscopic and spinal cord stimulation in the last ten years. Regardless of intervention technique or preoperative diagnosis, 87% of patients showed improvement with treatment. CONCLUSIONS: The literature surrounding NC intervention techniques is reviewed. Recent advancements and the wide range of craniofacial pain syndromes for which these interventions show potential efficacy are discussed. New and less invasive techniques continue to emerge as putative therapeutic options. However, prospective studies are lacking. Furthermore, the evidence supporting even well-established techniques remains of poor quality. Future work should be prospective, use standard outcome reporting, and address efficacy comparisons between intervention type and preoperative diagnosis.

Hemodynamic and Anatomical Factors in Arteriovenous Malformation Clinical Presentation: 45 Case Studies.

BACKGROUND: Hemodynamic factors have been implicated in hemorrhage from cerebral arteriovenous malformations (AVMs). The goal of this endovascular study is to analyze the hemodynamic variability in AVM feeders in a balanced group of ruptured and unruptured AVMs of various sizes and at both superficial and deep locations. METHODS: We monitored feeder artery pressure (FP) using microcatheters in 45 patients with AVMs (16 with hemorrhage, 29 without) during superselective angiography and AVM embolization. RESULTS: Mean FP was 49 mm Hg. Significant determinants of FP were the systemic pressure (p < 0.001), AVM size (p = 0.03), and the distance of the microcatheter tip from the Circle of Willis (p = 0.06), but not the presence of hemorrhage, patient age, or feeder artery diameter. The FP in ruptured AVMs was 7 mm Hg higher than in unruptured ones (53.8 mm Hg vs. 47.1 mm Hg, p = 0.032). The presence or absence of venous outflow stenosis and the position of the AVM nidus (superficial or deep to the cortical surface) were important anatomical predictors of AVM presentation. CONCLUSION: The pressure in the feeding artery supplying an AVM is the result of factors which include the systemic arterial pressure, the size of the AVM nidus, and the distance of the AVM from the Circle of Willis. The correlation between these variables makes it difficult to study the risk of hemorrhage as a function of a single factor, which may account for the variation in the conclusions of previous studies.

A Canadian National Survey of the Neurosurgical Management of Intracranial Abscesses.

OBJECTIVE: Intracerebral abscess is a life-threatening condition for which there are no current, widely accepted neurosurgical management guidelines. The purpose of this study was to investigate Canadian practice patterns for the medical and surgical management of primary, recurrent, and multiple intracerebral abscesses. METHODS: A self-administered, cross-sectional, electronic survey was distributed to active staff and resident members of the Canadian Neurosurgical Society and Canadian Neurosurgery Research Collaborative. Responses between subgroups were analyzed using the Chi-square test. RESULTS: In total, 101 respondents (57.7%) completed the survey. The majority (60.0%) were staff neurosurgeons working in an academic, adult care setting (80%). We identified a consensus that abscesses >2.5 cm in diameter should be considered for surgical intervention. The majority of respondents were in favor of excising an intracerebral abscess over performing aspiration if located superficially in non-eloquent cortex (60.4%), located in the posterior fossa (65.4%), or causing mass effect leading to herniation (75.3%). The majority of respondents were in favor of reoperation for recurrent abscesses if measuring greater than 2.5 cm, associated with progressive neurological deterioration, the index operation was an aspiration and did not include resection of the abscess capsule, and if the recurrence occurred despite prior surgery combined with maximal antibiotic therapy. There was no consensus on the use of topical intraoperative antibiotics. CONCLUSION: This survey demonstrated heterogeneity in the medical and surgical management of primary, recurrent, and multiple brain abscesses among Canadian neurosurgery attending staff and residents.

High-fidelity, simulation-based microsurgical training for neurosurgical residents.

OBJECTIVE: Simulation is increasingly recognized as an important supplement to operative training. The live rat femoral artery model is a well-established model for microsurgical skills simulation. In this study, the authors present an 11-year experience incorporating a comprehensive, longitudinal microsurgical training curriculum into a Canadian neurosurgery program. The first goal was to evaluate training effectiveness, using a well-studied rating scale with strong validity. The second goal was to assess the impact of the curriculum on objective measures of subsequent operating room performance during postgraduate year (PGY)-5 and PGY-6 training. METHODS: PGY-2 neurosurgery residents completed a 1-year curriculum spanning 17 training sessions divided into 5 modules of increasing fidelity. Both perfused duck wing and live rat vessel training models were used. Three modules comprised live microvascular anastomosis. Trainee performance was video recorded and blindly graded using the Objective Structured Assessment of Technical Skills Global Rating Scale. Eleven participants who completed the training curriculum and 3 subjects who had not participated had their subsequent operative performances evaluated when they were at the PGY-5 and PGY-6 levels. RESULTS: Eighteen participants completed 106 microvascular anastomoses during the study. There was significant improvement in 6 measurable skills during the curriculum. The mean overall score was significantly higher on the fifth attempt compared with the first attempt for all 3 live anastomotic modules (p < 0.001). Each module had a different improvement profile across the skills assessed. Those who completed the microvascular skills curriculum demonstrated a greater number of independent evaluations during superficial surgical exposure, deep exposure, and primary maneuvers at the PGY-5 and PGY-6 levels. CONCLUSIONS: High-fidelity microsurgical simulation training leads to significant improvement in microneurosurgical skills. Transfer of acquired skills to the operative environment and durability for at least 3 to 4 years show encouraging preliminary results and are subject to ongoing investigation.

Evidence of multiple hepatic mechanisms to mobilize docosahexaenoic acid into dam plasma during pregnancy in chow-fed sprague dawley rats.

Fetal brain growth requires considerable amounts of docosahexaenoic acid (DHA) during late pregnancy that is associated with increased maternal/dam plasma levels of PC 16:0_22:6 (palmitoyl docosahexaenoyl phosphatidylcholine). While biosynthesis of DHA during pregnancy is upregulated, the mechanisms responsible for the incorporation of dam DHA into PC 16:0_22:6 are not understood. The present study used a discovery approach combining untargeted lipidomics of plasma and liver (n = 3/group) with semi-targeted qPCR of hepatic gene products (n = 6/group) to identify metabolic pathways related to DHA metabolism, with a hypothesis that an upregulated acyltransferase involved in PC remodeling would be identified. Sprague Dawley rats were fed a commercial rodent chow throughout the study and samples were collected before pregnancy (baseline), at 15 and 20 days of pregnancy, and 7 days postpartum. Plasma and hepatic PC 16:0_22:6 was significantly increased (by 79% and 194%, respectively) at day 20 of pregnancy. An increase in hepatic DG (diacylglycerol) 16:0_22:6 (by 243%) and significant decreases in Pla2G15 (0.4-fold) and Pla2G16 (0.6-fold) at day 20 of pregnancy, no changes in Lpcat1-4, and an abundant pool of hepatic pool PE (phosphatidylethanolamine) 16:0_22:6 suggest that plasma PC 16:0_22:6 is not being produced by fatty acyl remodeling during pregnancy. The increase in plasma PC 16:0_22:6 during pregnancy appears to be due to an increase in de novo synthesis of PC and both the CDP-choline and phosphatidylcholine methyltransferase pathways are implicated. There was also evidence suggesting channeling of DHA into PC and lipoprotein assembly may be occurring. Targeted research is necessary to confirm these findings, but the results of this study indicate metabolic adaptions to enable maternal/dam resiliency towards meeting the fetal/pup demand for DHA during pregnancy.

Acute Hemorrhagic Encephalitis Related to COVID-19.

PURPOSE OF REVIEW: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the most critical public health challenge in recent history. In this report, we present a case of suspected acute hemorrhagic encephalitis with bilateral intracranial hemorrhages associated with coronavirus disease 2019 (COVID-19) infection. RECENT FINDINGS: A 48-year-old female COVID-19-positive patient developed acute changes in her neurologic status. A head CT with CT angiography demonstrated extensive bilateral parietal and occipital intraparenchymal hemorrhage with intraventricular extension and acute hydrocephalus. The patient was treated with an external ventricular drain, and a CSF sample was tested for SARS-CoV-2 but was found to be negative. SUMMARY: The underlying mechanism for developing acute hemorrhagic encephalitis in viral illnesses may be autoimmune in nature and warrants further investigation. The initial neurologic presentation of COVID-19-related hemorrhagic encephalitis is altered level of consciousness, which may prompt further neurologic examination and imaging to exclude this feature.

A safety review of approved intrathecal analgesics for chronic pain management.

Introduction: Intrathecal (IT) drug therapy is an effective treatment option for patients with chronic pain of malignant or nonmalignant origin, with an established safety profile and fewer adverse effects compared to oral or parenteral pain medications. Morphine (a µ-opioid receptor agonist) and ziconotide (a non-opioid calcium channel antagonist) are the only IT agents approved by the U.S. Food and Drug Administration for the treatment of chronic pain. Although both are considered first-line IT therapies, each drug has unique properties and considerations.Areas Covered: This review will evaluate the pivotal trials that established the use of morphine and ziconotide as first-line IT therapy for patients with chronic pain, as well as safety and efficacy data generated from various retrospective and prospective studies.Expert Opinion: Morphine and ziconotide are effective IT therapies for patients with chronic malignant or nonmalignant pain that is refractory to other interventions. IT ziconotide is recommended as a first-line therapy due to its efficacy and avoidance of many adverse effects commonly associated with opioids. The use of IT morphine is also considered first-line; however, the risks of respiratory depression, withdrawal with drug discontinuation or pump malfunction, and the development of tolerance require careful patient selection and management.

Dorsal Root Entry Zone Lesioning for Brachial Plexus Avulsion Injuries: Case Series and Literature Review.

Introduction: Brachial plexus avulsion (BPA) injuries commonly occur secondary to motor vehicle collisions, usually in the young adult population. These injuries are associated with significant morbidity, and up to 90% of patients suffer from deafferentation pain. Neuromodulation procedures can be efficacious in the treatment of refractory neuropathic pain, although the treatment of pain due to BPA can be challenging. Dorsal root entry zone (DREZ) lesioning is a classical and effective neurosurgical technique which has become underutilized in treating refractory root avulsion pain. Methods: A systematic review of the different technical nuances, procedural efficacy, and complication profiles regarding DREZ lesioning for BPA injuries in the literature is included. We also present an institutional case series of 7 patients with BPA injuries who underwent DREZ lesioning. Results: In the literature, 692 patients were identified to have undergone DREZ lesioning for pain related to BPA. In 567 patients, the surgery was successful in reducing pain intensity by over 50% in comparison to baseline (81.9%). Complications included transient motor deficits (11%) and transient sensory deficits (11%). Other complications including permanent disability, cardiovascular complications, infections, or death were rare (<1.9%). In our case series, all but one patient achieved >50% reduction in pain intensity, with the mean pre-operative pain of 7.9 ± 0.63 (visual analog scale) reduced to 2.1 ± 0.99 at last follow-up (p < 0.01). Conclusion: Both the literature and the current case series demonstrate excellent pain severity reduction following DREZ ablation for deafferentation pain secondary to BPA.

Cranial nerve and intramedullary spinal malignant peripheral nerve sheath tumor associated with neurofibromatosis-1.

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are uncommon but aggressive neoplasms associated with radiation exposure and neurofibromatosis Type I (NF1). Their incidence is low compared to other nervous system cancers, and intramedullary spinal lesions are exceedingly rare. Only a few case reports have described intramedullary spinal cord MPNST. Case Description: We describe the clinical findings, management, and outcome of a young patient with NF1 who developed aggressive cranial nerve and spinal MPNST tumors. This 35-year-old patient had familial NF1 and a history of optic glioma treated with radiation therapy (RT). She developed a trigeminal MPNST that was resected and treated with RT. Four years later, she developed bilateral lower extremity deficits related to an intramedullary cervical spine tumor, treated surgically, and found to be a second MPNST. Conclusion: To the best of our knowledge, this is the first report of cranial nerve and intramedullary spinal MPNSTs manifesting in a single patient, and only the third report of a confined intramedullary spinal MPNST. This unusual case is discussed in the context of a contemporary literature review.

Iatrogenic pseudoaneurysms associated with cerebrospinal fluid diversion procedures.

BACKGROUND: Cerebrospinal fluid diversion procedures, including ventriculoperitoneal (VP) shunt and external ventricular drain insertion, are common treatments for hydrocephalus. Common complications include obstruction, infection, and hemorrhage. Pseudoaneurysm formation secondary to catheter insertion is a distinctly rare complication, and usually involves the anterior cerebral artery or branches of the external carotid artery (superficial temporal artery or middle meningeal artery). CASE DESCRIPTION: We present the case of a fusiform pseudoaneurysm in a 36-year-old female, which arose from a branch of the middle cerebral artery following VP shunt insertion. Parenchymal and intraventricular hemorrhage at the catheter insertion site developed 15 days postoperatively. The VP shunt was removed, and the aneurysmal segment was coagulated and occluded. Use of a limited dural opening during ventricular catheter placement may have been a factor in pseudoaneurysm formation. CONCLUSIONS: The literature regarding this rare complication is reviewed. Careful consideration should be given to vascular anatomy when planning shunt insertions, and a cruciate dural opening for cortical visualization and coagulation may help avoid this complication. Prompt identification and management of iatrogenic pseudoaneurysms is essential to avoid re-bleeding and associated hemorrhagic complications.

Concentrations of docosahexaenoic acid are reduced in maternal liver, adipose, and heart in rats fed high-fat diets without docosahexaenoic acid throughout pregnancy.

Fetal accretion for DHA is high during late pregnancy due to the brain growth spurt. Prior evidence suggests that DHA is mobilized from maternal liver and adipose to meet fetal accretion and physiological requirements. However, changes in the DHA levels of various maternal tissues throughout pregnancy and into lactation of mothers on diets with and without dietary DHA, and with a background dietary fatty acid profile that resembles human intake has not been examined. Sprague Dawley rats were fed a total western diet with (TWD + ) or without DHA (TWD-) along with a commercial rodent chow control (Chow) throughout pregnancy and postpartum. The fatty acid compositions of adipose, brain, heart, liver, erythrocytes, and plasma were determined before pregnancy, at 15 and 20 days of pregnancy, and 7 days postpartum. The placenta, fetuses, and pups were also examined when available. Maternal DHA concentrations were increased in plasma at 20 days pregnancy in all the diets with TWD + > Chow > TWD-. Maternal DHA concentrations in the TWD- group were lower in adipose throughout pregnancy as compared with the other diets. At postpartum, DHA concentrations decreased below baseline levels in the heart of the TWD- and Chow dams and the liver of the TWD- dams. Whole body DHA concentrations of the fetuses did not differ but there was evidence of decreased DHA in the whole body and tissues of the TWD- and Chow 7d old pups. In conclusion, it appears that in this rodent model of pregnancy, maternal adaptations were made to meet fetal DHA requirements, but they may compromise maternal DHA status and the ability to deliver DHA during lactation.

PEMT, Δ6 desaturase, and palmitoyldocosahexaenoyl phosphatidylcholine are increased in rats during pregnancy.

DHA is important for fetal neurodevelopment. During pregnancy, maternal plasma DHA increases, but the mechanism is not fully understood. Using rats fed a fixed-formula diet (DHA as 0.07% total energy), plasma and liver were collected for fatty acid profiling before pregnancy, at 15 and 20 days of pregnancy, and 7 days postpartum. Phosphatidylethanolamine methyltransferase (PEMT) and enzymes involved in PUFA synthesis were examined in liver. Ad hoc transcriptomic and lipidomic analyses were also performed. With pregnancy, DHA increased in liver and plasma lipids, with a large increase in plasma DHA between day 15 and day 20 that was mainly attributed to an increase in 16:0/DHA phosphatidylcholine (PC) in liver (2.6-fold) and plasma (3.9-fold). Increased protein levels of Δ6 desaturase (FADS2) and PEMT at day 20 and increased Pemt expression and PEMT activity at day 15 suggest that during pregnancy, both DHA synthesis and 16:0/DHA PC synthesis are upregulated. Transcriptomic analysis revealed minor changes in the expression of genes related to phospholipid synthesis, but little insight on DHA metabolism. Hepatic PEMT appears to be the mechanism for increased plasma 16:0/DHA PC, which is supported by increased DHA biosynthesis based on increased FADS2 protein levels.

A role for activated Cdc42 in glioblastoma multiforme invasion.

Cdc42 is a Rho-GTPase which plays a major role in regulating cell polarity and migration by specifying the localization of filopodia. However, the role of Cdc42 in GBM invasion has not been thoroughly investigated. We generated stable doxycycline-inducible clones expressing wild type (WT)-, constitutively active (CA)-, and dominant negative (DN)-Cdc42 in three different human glioma cell lines. Expression of CA-Cdc42 significantly increased the migration and invasive properties of malignant glioma cells compared to WT and DN-Cdc42 cell clones, and this was accompanied by a greater number of filopodia and focal adhesion structures which co-localize with phosphorylated focal adhesion kinase (FAK). By mass spectrometry and immunoprecipitation studies, we demonstrated that activated Cdc42 binds to IQGAP1. When implanted orthotopically in mice, the CA-Cdc42 expressing glioma cells exhibited enhanced local migration and invasion, and led to larger tumors, which significantly reduced survival. Using the Cancer Genome Atlas dataset, we determined that high Cdc42 expression is associated with poorer progression free survival, and that Cdc42 expression is highest in the proneural and neural subgroups of GBM. In summary, our studies demonstrate that activated Cdc42 is a critical determinant of the migratory and invasive phenotype of malignant gliomas, and that its effect may be mediated, at least in part, through its interaction with IQGAP1 and phosphorylated FAK.

PINK1 Is a Negative Regulator of Growth and the Warburg Effect in Glioblastoma.

Proliferating cancer cells are characterized by high rates of glycolysis, lactate production, and altered mitochondrial metabolism. This metabolic reprogramming provides important metabolites for proliferation of tumor cells, including glioblastoma. These biological processes, however, generate oxidative stress that must be balanced through detoxification of reactive oxygen species (ROS). Using an unbiased retroviral loss-of-function screen in nontransformed human astrocytes, we demonstrate that mitochondrial PTEN-induced kinase 1 (PINK1) is a regulator of the Warburg effect and negative regulator of glioblastoma growth. We report that loss of PINK1 contributes to the Warburg effect through ROS-dependent stabilization of hypoxia-inducible factor-1A and reduced pyruvate kinase muscle isozyme 2 activity, both key regulators of aerobic glycolysis. Mechanistically, PINK1 suppresses ROS and tumor growth through FOXO3a, a master regulator of oxidative stress and superoxide dismutase 2. These findings highlight the importance of PINK1 and ROS balance in normal and tumor cells. PINK1 loss was observed in a significant number of human brain tumors including glioblastoma (n > 900) and correlated with poor patient survival. PINK1 overexpression attenuates in vivo glioblastoma growth in orthotopic mouse xenograft models and a transgenic glioblastoma model in Drosophila Cancer Res; 76(16); 4708-19. ©2016 AACR.

Epithelial Cell Transforming 2 and Aurora Kinase B Modulate Formation of Stress Granule-Containing Transcripts from Diverse Cellular Pathways in Astrocytoma Cells.

Stress granules are small RNA-protein granules that modify the translational landscape during cellular stress to promote survival. The RhoGTPase RhoA is implicated in the formation of RNA stress granules. Our data demonstrate that the cytokinetic proteins epithelial cell transforming 2 and Aurora kinase B (AurkB) are localized to stress granules in human astrocytoma cells. AurkB and its downstream target histone-3 are phosphorylated during arsenite-induced stress. Chemical (AZD1152-HQPA) and siRNA inhibition of AurkB results in fewer and smaller stress granules when analyzed using high-throughput fluorescent-based cellomics assays. RNA immunoprecipitation with the known stress granule aggregates TIAR and G3BP1 was performed on astrocytoma cells, and subsequent analysis revealed that astrocytoma stress granules harbor unique mRNAs for various cellular pathways, including cellular migration, metabolism, translation, and transcriptional regulation. Human astrocytoma cell stress granules contain mRNAs that are known to be involved in glioma signaling and the mammalian target of rapamycin pathway. These data provide evidence that RNA stress granules are a novel form of epigenetic regulation in astrocytoma cells, which may be targetable by chemical inhibitors and enhance astrocytoma susceptibility to conventional therapy, such as radiation and chemotherapy.

Low Grade Gliomas in Children.

Gliomas represent the most common solid tumor of the nervous system, and can occur as both low and high-grade tumors. Current risk stratification and treatment approaches rely heavily on the morphological classification of gliomas whereby low-grade gliomas have an excellent prognosis, particularly pilocytic astrocytomas, while high-grade gliomas have a poor prognosis. The past decade has witnessed a dramatic increase in scholars' knowledge of the biology of pediatric low-grade gliomas particularly through the advent of integrated genomics and next generation sequencing. Indeed, many of these biological advances are changing treatment paradigms, particularly in low-grade gliomas, where rationale targeted therapies are currently being explored in clinical trials. In this review the authors summarize the current approach to pediatric low grade gliomas and outline the biological advances over the past 10 years, which will be driving the next generation of clinical trials.

Omega-3 polyunsaturated fatty acid blood biomarkers increase linearly in men and women after tightly controlled intakes of 0.25, 0.5, and 1 g/d of EPA + DHA.

Blood levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been related to coronary heart disease risk. Understanding the response of EPA + DHA in blood to dietary intake of EPA + DHA would facilitate the use of blood measures as markers of adherence and enable the development of dietary recommendations. The objective of this study is examine the blood response to intakes of EPA + DHA ≤1 g/d with an intervention designed for dietary adherence. It was hypothesized this relationship would be linear and that intakes of EPA + DHA <1 g/d would result in blood levels below those associated with the highest level of protection for cardiovascular events. Background EPA + DHA intake of men and women (n = 20) was determined by food frequency questionnaire and adherence was monitored by weekly fingertip blood sampling for fatty acid determinations. Participants consumed nutraceuticals to achieve intakes of 0.25 g/d and 0.5 g/d EPA + DHA for successive four-week periods. A subgroup (n = 5) had intakes of 1.0 g/d EPA + DHA for an additional 4 weeks. Fatty acid composition of whole blood, erythrocytes, and plasma phospholipids were determined at each time point. Blood levels of EPA and DHA increased linearly in these pools. A comprehensive review of the literature was used to verify the blood-intake relationship. Blood levels of long chain omega-3 polyunsaturated fatty acids reached blood levels associated with the highest levels of primary cardiac arrest reduction and sudden cardiac death risk only with intakes of 1.0 g/d of EPA + DHA. The blood biomarker response to intakes of EPA + DHA ≤1 g/d is linear in a small but highly adherent study sample and this information can assist in determining adherence in clinical studies and help identify dietary intake targets from associations between blood and disease.