Lymphatic Education
& Research Network

Latest Research

• A Neuro-Lympho-Vascular Component of Multiple Sclerosis and Alzheimer’s Disease?

  Lymphatic vasculature drains interstitial fluids, which contain the tissue’s waste products, and ensures immune surveillance of the tissues, allowing immune cell recirculation. Until recently, the CNS was considered to be devoid of a conventional lymphatic vasculature. The recent discovery in the meninges of a lymphatic network that drains the CNS calls into question classic models for the drainage of macromolecules and immune cells from the CNS. In the context of neurological disorders, the presence of a lymphatic system draining the CNS potentially offers a new player and a new avenue for therapy. In this review, we will attempt to integrate the known primary functions of the tissue lymphatic vasculature that exists in peripheral organs with the proposed function of meningeal lymphatic vessels in neurological disorders, specifically multiple sclerosis and Alzheimer’s disease. We propose that these (and potentially other) neurological afflictions can be viewed as diseases with a neuro-lympho-vascular component and should be therapeutically targeted as such.

  Authors:  Antoine Louveau, Sandro Da Mesquita, Jonathan Kipnis

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• How Do Meningeal Lymphatic Vessels Drain the CNS?

  The many interactions between the nervous and the immune systems, which are active in both physiological and pathological states, have recently become more clearly delineated with the discovery of a meningeal lymphatic system capable of carrying fluid, immune cells, and macromolecules from the central nervous system (CNS) to the draining deep cervical lymph nodes. However, the exact localization of the meningeal lymphatic vasculature and the path of drainage from the cerebrospinal fluid (CSF) to the lymphatics remain poorly understood. Here, we discuss the potential differences between peripheral and CNS lymphatic vessels and examine the purported mechanisms of CNS lymphatic drainage, along with how these may fit into established patterns of CSF flow.

  Trends

  Functional classic lymphatic vessels exist in the dura, and can function to drain fluid and immune cells from the meninges, parenchyma, and CSF.

  The meningeal lymphatic system is necessary for the efficient clearance of brain ISF, and may be a common pathway for removal of wastes initially cleared from brain parenchyma through the glymphatic system of CSF–interstitial fluid (ISF) exchange.

  The precise location of meningeal lymphatic vessels within the layers of the meninges needs to be further investigated.

  The hemodynamics of the flow and access of the CSF to meningeal lymphatic vessels are still poorly understood.

  Authors:  Daniel Raper, Antoine Louveau, Jonathan Kipnis

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• Structural and functional features of central nervous system lymphatic vessels

  One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment1, 2, 3, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood4, 5, 6. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.

  Authors:  Antoine Louveau, Igor Smirnov, Timothy J. Keyes, Jacob D. Eccles, Sherin J. Rouhani, J. David Peske, Noel C. Derecki, David Castle, James W. Mandell, Kevin S. Lee, Tajie H. Harris & Jonathan Kipnis

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• The Cutaneous, Net Clinical, and Health Economic Benefits of Advanced Pneumatic Compression Devices

  Authors: Pinar Karaca-Mandic, PhD; Alan T. Hirsch, MD; Stanley G. Rockson, MD; Sheila H. Ridner, PhD, RN

  Publication Abstract:

  Importance: The prevalence and clinical burden of lymphedema is known to be increasing. Nevertheless, evidence-based comparative effectiveness data regarding lymphedema therapeutic interventions have been poor.

  Objective: To examine the impact of an advanced pneumatic compression device (APCD) on cutaneous and other clinical outcomes and health economic costs in a representative privately insured population of lymphedema patients.

  Design, Setting, and Participants: Retrospective analysis of a deidentified private insurance database from 2007 through 2013, and multivariate regression analysis comparing outcomes for the 12 months before and after APCD purchase, adjusting for baseline patient characteristics. Patients with lymphedema who received an APCD who were commercially insured and Medicare managed care enrollees from a large, national US managed care health insurer. The study population was evaluated as cancer-related and non–cancer-related lymphedema cohorts.

  Intervention: Receipt of an APCD.

  Main Outcomes and Measures: Rates of cellulitis, use of lymphedema-related manual therapy, outpatient hospital visits, and inpatient hospitalizations. Lymphedema-related direct costs were measured for home health care, hospital outpatient care, office visits, emergency department use, and inpatient care.

  Results: The study sample included 718 patients (374 in the cancer cohort and 344 in the noncancer cohort). In both cohorts, use of an APCD was associated with similar reductions in adjusted rates of cellulitis episodes (from 21.1% to 4.5% in the cancer cohort and 28.8% to 7.3% in the noncancer cohort; P < .001 for both), lymphedema-related manual therapy (from 35.6% to 24.9%in the cancer cohort and 32.3% to 21.2% in the noncancer cohort; P < .001 for both), and outpatient visits (from 58.6% to 41.4% in the cancer cohort and 52.6% to 31.4% in the noncancer cohort; P < .001 for both). Among the cancer cohort, total lymphedema-related costs per patient, excluding medical equipment costs, were reduced by 37% (from $2597 to $1642, P = .002). The corresponding decline in costs for the noncancer cohort was 36% (from $2937 to $1883, P = .007).

  Conclusions and Relevance: The study found an association between significant reductions in episodes of cellulitis (cancer vs noncancer cohorts) and outpatient care and costs of APCD acquisition within a 1-year time frame in patients with both cancer-related and non–cancer-related lymphedema.

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• Lymphedema Prevalence and Treatment Benefits in Cancer: Impact of a Therapeutic Intervention

  Full Title:  Lymphedema Prevalence and Treatment Benefits in Cancer: Impact of a Therapeutic Intervention on Health Outcomes and Costs

  Authors:  Kimberly M. Brayton, Alan T. Hirsch, Patricia J. O′Brien, Andrea Cheville, Pinar Karaca-Mandic, Stanley G. Rockson

  Background:  Lymphedema is a common complication of cancer therapeutics; its prevalence, treatment outcomes, and costs have been poorly defined. The objective of this study was to examine lymphedema prevalence among cancer survivors and to characterize changes in clinical outcomes and costs associated with a defined therapeutic intervention (use of a pneumatic compression devices [PCD]) in a representative, privately insured population.

  Methods and Findings:  Retrospective analysis of de-identified health claims data from a large national insurer for calendar years 2007 through 2013. Patients were required to have 12 months of continuous insurance coverage prior to PCD receipt (baseline), as well as a 12-month follow-up period. Analyses were performed for individuals with cancer-related lymphedema (n = 1,065). Lymphedema prevalence was calculated: number of patients with a lymphedema claim in a calendar year divided by total number of enrollees. The impact of PCD use was evaluated by comparing rates of a pre-specified set of health outcomes and costs for the 12 months before and after, respectively, PCD receipt. Lymphedema prevalence among cancer survivors increased from 0.95% in 2007 to 1.24% in 2013. PCD use was associated with decreases in rates of hospitalizations (45% to 32%, p<0.0001), outpatient hospital visits (95% to 90%, p<0.0001), cellulitis diagnoses (28% to 22%, p = 0.003), and physical therapy use (50% to 41%, p<0.0001). The average baseline health care costs were high ($53,422) but decreased in the year after PCD acquisition (−$11,833, p<0.0001).

  Conclusions:  Lymphedema is a prevalent medical condition that is often a defining attribute of cancer survivorship. The problem is associated with high health care costs; Treatment (in this instance, use of PCD) is associated with significant decreases in adverse clinical outcomes and costs.

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• Quantitative Contrast-Enhanced Magnetic Resonance Lymphangiography…

  Quantitative Contrast-Enhanced Magnetic Resonance Lymphangiography of the Upper Limbs in Breast Cancer Related Lymphedema: An Exploratory Study

  Background: Contrast-Enhanced Magnetic Resonance Lymphangiography (CE-MRL) presents some limitations: (i) it does not quantify lymphatic functionality; and (ii) enhancement of vascular structures may confound image interpretation. Furthermore, although CE-MRL is well described in the published literature for the lower limbs, there is a paucity of data with regards to its use in the upper limbs. In this proof-of-principle study, we propose a new protocol to perform CE-MRL in the upper limbs of patients with breast cancer-related lymphedema (BCRL) which addresses these limitations.

  Methods and Results: CE-MRL was performed using a previously published (morphological) protocol and the proposed protocol (quantitative) on both the ipsilateral (abnormal) and contralateral (normal) arms of patients with BCRL. The quantitative protocol employs contrast agent (CA) intradermal injections at a lower concentration to prevent T2*-related signal decay. Both protocols provided high-resolution three-dimensional images of upper limb lymphatic vessels. CA uptake curves were utilized to distinguish between lymphatic vessels and vascular structures. The quantitative protocol minimized venous enhancement and avoided spurious delays in lymphatic enhancement due to short T2* values, enabling correct CA uptake characterization. The quantitative protocol was therefore employed to measure the lymphatic fluid velocity, which demonstrated functional differences between abnormal and normal arms. The velocity values were in agreement with previously reported lymphoscintigraphy and near infra-red lymphangiography measurements.

  Conclusions: This work demonstrated the feasibility of CE-MRL of the upper limbs in patients with BRCL, introducing an advanced imaging and analysis protocol suitable for anatomical and functional study of the lymphatic system.

   

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• A High-Salt Diet Differentially Modulates Mechanical Activity ...

  A High-Salt Diet Differentially Modulates Mechanical Activity of Afferent and Efferent Collecting Lymphatics in Murine Iliac Lymph Nodes

  Background: The lymphatic system contributes to fluid homeostasis in various tissues. Recent evidence suggests that lymphangiogenesis induced by a high-salt diet (HSD) is associated with blood pressure regulation. Lymph nodes, located along lymphatic pathways, are not only important secondary lymphoid tissues for cancer metastasis, inflammation, and immune responses, but are also important for fluid homeostasis. Afferent lymphatics collect lymph from the pre-nodal area and efferent lymphatics drain lymph out of the lymph nodes. However, the difference in mechanical activity between afferent and efferent lymphatics and the effect of a HSD on these vessels have not been shown.

  Methods and Results: Changes in mechanical activity of isolated afferent and efferent lymphatics in normal salt diet (NSD) and 4-week HSD mice in response to increases in intraluminal pressures from 3 to 7 cmH2O were measured using video-microscopy. The higher intramural pressure equivalently decreased pumping activity of afferent and efferent lymphatics in NSD mice. A HSD suppressed the amplitude, ejection fraction, and stroke volume of afferent lymphatics, leading to marked reductions in pumping activity. In contrast, the pumping activities of efferent lymphatics were resistant to a HSD and were preserved by enhancing the contraction frequency.

  Conclusions: A HSD differentially modulated the mechanical activity of afferent and efferent collecting lymphatics in murine iliac lymph nodes.

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• Dietary Sodium and Lymphatic Contractile Activity

  Recent published investigations suggest that there may be an important link between hypertension and lymphatic vascular function. This, therefore establishes a hypothetical link between lymphatic function and the attendant hypertensive risks of coronary ischemia, stroke, heart failure and renal insufficiency.

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• A Pilot Randomized Trial Evaluating Low-Level Laser Therapy

  To examine the impact of advanced practice nurse (APN) administered low level laser therapy (LLLT) as both a stand-alone and complementary treatment for arm volume, symptoms, and quality of life (QOL) in women with breast cancer related lymphedema.

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• Effect of low-level laser therapy on pain and swelling in women with BCRL

  This study aims to examine literature on effectiveness of low-level laser therapy (LLLT) in reducing limb volume and pain in adults with breast cancer-related lymphedema (BCRL).

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