Background
Lymphedema is characterized by swelling of the soft tissue secondary to obstruction of lymphatic drainage. Lymphatic obstruction causes an increase in the protein content of the extravascular tissue with subsequent retention of water. The increase in the extravascular protein stimulates proliferation of fibroblasts, organization of the fluid, and development of a "woody feeling" nonpitting swelling of the affected extremity. Fibrosis also obstructs the lymphatic channels and leads to increased protein concentration in the tissues, continuing this cycle. Lymphedema opens channels in the integument and allows bacteria to enter the subcuticular space, which overwhelms host defenses and leads to cellulitis of the extremity.
Lymphedema is classified into primary and secondary forms. Secondary lymphedema occurs as a result of obstruction of lymphatic flow by known mechanisms, ie, filariasis, silica, obstruction by a proximal mass, postsurgical mechanisms (eg, mastectomy), and fibrosis secondary to chronic infections.
Primary lymphedema is divided into 3 groups based on age of onset.[1] Congenital lymphedema that is present at birth and associated with an autosomal dominant familial history is called Milroy disease.[2] Lymphedema praecox (Meige disease) occurs after birth but before 35 years; the age of onset is generally in adolescence.[3] Lymphedema tarda occurs in individuals older than 35 years. Of patients with primary lymphedema, 10% have Milroy disease, 80% have lymphedema praecox, and 10% have lymphedema tarda (manifesting in persons older than 35 y). Connell et al proposed a classification system of the primary lymphatic dysplasias that is based on phenotype rather than age of onset.[4]
A related article posted on Medscape is " Diagnosis and Management of Lymphatic Vascular Disease."
An image depicting the lymphatic system can be seen below.
View Image | Lymphatic system, anterior view. |
Pathophysiology
Hypoplasia, dilation, and tortuosity of lymphatic structures characterize primary lymphedema. Failure of adequate clearance of lymphatic fluid leads to accumulation of protein in the extracellular fluid. Fibroblasts are stimulated, and the swelling becomes organized and nonpitting. Obstruction of normal lymph flow predisposes patients to recurrent infection with streptococci or staphylococci. These infections cause more lymphatic destruction and predispose patients to prolonged episodes of lymphedema and recurrent bacterial infection.[5]
A tyrosine kinase receptor specific for lymphatic vessels has been reported to be abnormally phosphorylated in patients with Milroy disease. The gene for this disease, vascular endothelial growth factor receptor 3, VEGFR3 (FLT4),[6, 7, 8, 9] has been mapped to the telomeric part of chromosome arm 5q in the region 5q34-q35.[10] VEGFR3 is expressed in the adult lymphatic endothelial cells. The literature suggests that failure of lymph absorption is not due to the absence of lymphatic drainage routes but due to dysfunction of the lymphatics that are present.[11] Examination of patients with Milroy disease by fluorescence microlymphangiography demonstrated a high rate of functional failure of the lymphatic system.[12] Studies in transgenic mice with overexpression of VEGFR3 ligands demonstrate the formation of new hyperplastic lymphatics. Induction of this gene may provide a potential target for future interventions in this patient population.
Epidemiology
Frequency
United States
The primary lymphedemas occur in 1 of 10,000 individuals. Milroy disease is inherited as an autosomal dominant condition associated with variable penetrance. It is not observed as commonly as lymphedema praecox (Meige disease), which constitutes 80% of cases of primary lymphedema. Actual incidence of Milroy disease is unknown because most patients have been reported in small case-based studies. Approximately 200 cases have been described in the literature.
Mortality/Morbidity
Primary lymphedema usually does not progress. The condition stabilizes after several years of activity.
Patients may have recurrent streptococcal cellulitis and lymphangitis, with subsequent hospitalizations for antibiotic therapy.
A rare complication is the appearance of lymphangiosarcoma or angiosarcoma in patients with persistent lymphedema.[13] Some patients may develop protein-losing enteropathy and visceral involvement. Chylous ascites and chylothorax rarely occur.
Race
Milroy disease has no known racial predilection.
Sex
Milroy disease affects both sexes; however, 70-80% of cases occur in females.
Age
By definition, Milroy disease occurs in infants and is present at birth. Lymphedema praecox occurs in individuals younger than 35 years, usually in adolescents.
Histologic Findings
Early in the disease, lymphatic vessels are conspicuously absent upon biopsy. Late in the disease, histology shows lymphangiectasia and fibrosis involving the subcutaneous skin.
Medical Care
Treatment of patients with hereditary lymphedema is primarily directed against the prevention of infection and the control of local complications of limb swelling. Studies in mice, however, suggest that induced overexpression of VEGFR3 ligands stimulate the growth of functional lymphatic vessels.[17] An increase in lymphatics would benefit patients with primary and secondary lymphedema.
Exercise and elevation of the extremity promote movement of fluid away from the lower extremity.
Elastic stockings and bandages are applied in a gradient fashion, with the highest compression distally and no constriction points.
Gentle massage or pneumatic compression can be used.
Proper skin hygiene and use of skin moisturizers prevents drying and fissuring of skin and subsequent bacterial skin infections.
Use an antistreptococcal antibiotic to treat recurrent cellulitis. Prophylactic antibiotic therapy, such as benzathine penicillin in low doses, may be used to prevent intermittent cellulitis. Antibiotics directed at prophylaxis should have good activity against Streptococcus pyogenes.
No medication treats or prevents Milroy disease. Complications of this disease, including cellulitis, bacteremia, and chylothorax, are treated as required. Benzopyrones, such as coumarin or diosmin, may stimulate proteolysis of tissue proteins.
Activity
Encourage patients to exercise after a graded support is applied to the involved extremity.
Medication Summary
No medication treats or prevents Milroy disease. Complications of this disease, including cellulitis, bacteremia, and chylothorax, are treated as required. Antistreptococcal antibiotics (eg, cefazolin, clindamycin) can be used to treat cellulitis. Monthly penicillin G benzathine injections may be required to prevent recurrent cellulitis.
Cefazolin (Ancef)
Clinical Context:
First-generation semisynthetic cephalosporin that arrests bacterial cell wall synthesis, inhibiting bacterial growth. Primarily active against skin flora, including Staphylococcus aureus. Typically used alone for skin and skin-structure coverage. IV and IM dosing regimens are similar.
Clindamycin (Cleocin)
Clinical Context:
Lincosamide for treatment of serious skin and soft tissue staphylococcal infections. Also effective against aerobic and anaerobic streptococci (but not enterococci). Inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
Penicillin G benzathine (Bicillin)
Clinical Context:
Interferes with synthesis of cell wall mucopeptides during active multiplication, which results in bactericidal activity. Used to treat syphilis and for prophylaxis of recurrent streptococcal infections.
Class Summary
Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of this clinical setting.
Warfarin (Coumadin)
Clinical Context:
Interferes with hepatic synthesis of vitamin K–dependent coagulation factors. Used for prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders. Tailor dose to maintain INR of 2-3.
Class Summary
May stimulate proteolysis of tissue proteins.
Author
Raphael J Kiel, MD, Associate Professor of Medicine, Wayne State University School of Medicine; Associate Professor of Medicine, Oakland University William Beaumont School of Medicine; Consulting Staff, Infectious Diseases Division, William Beaumont Hospital; Consulting Staff, Infectious Diseases Division Providence Hospital
Disclosure: Nothing to disclose.
Specialty Editors
Sat Sharma, MD, FRCPC, Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St Boniface General Hospital
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Gregg T Anders, DO, Medical Director, Great Plains Regional Medical Command , Brooke Army Medical Center; Clinical Associate Professor, Department of Internal Medicine, Division of Pulmonary Disease, University of Texas Health Science Center at San Antonio
Disclosure: Nothing to disclose.
Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, St Louis University School of Medicine
Disclosure: Nothing to disclose.
Chief Editor
Zab Mosenifar, MD, Director, Division of Pulmonary and Critical Care Medicine, Director, Women's Guild Pulmonary Disease Institute, Professor and Executive Vice Chair, Department of Medicine, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine
Disclosure: Nothing to disclose.
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