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To evaluate the impact of therapy and monitor the progression of filarial lymphedema, it is necessary to measure accurately the changes in limb edema volume. In this communication, we report the reliability of circumference measurements for recording volume changes. The measurements included the distal parts of limbs important for filarial lymphedema. In a series of 100 patients with unilateral lower limb lymphedema, both water displacement and circumference measurements were done. The results showed a significant correlation (r = 0.91; P = 0.0000) between the actual volume and that estimated by circumference measurement. Not only could volume of edema be calculated by circumference measurements, but the simple measurement of average circumference difference between the affected and normal limb accurately reflected the volume of actual edema.

Whereas clinical descriptions of grotesque lymphedema and standard light microscopy in human filariasis have elucidated the natural progression of this disease, the link between the nematode and vascular abnormalities including elephantiasis remains poorly understood. Accordingly, we examined the nature and distribution of lymphatic and blood vascular derangements in a variety of tissues and organs from 37 ferrets acutely and chronically infected with Brugia malayi and in 15 patients with Wuchereria bancrofti or Brugia malayi infestation (resected skin, subcutaneous tissue, and lymph nodes) using light and transmission electron microscopy, immunohistochemistry, and in vivo microscopy. In ferrets, eosinophilic abscesses and epithelioid and giant cell granulomas with fragmented worms in various stages of disintegration were found in multiple organs. Blood microvasculopathy consisted of endothelial hyperplasia, focal thickening and stenosis, vessel obliteration with marked perivascular infiltration of lymphocytes, plasma cells, eosinophils, and numerous large macrophages laden with a coarse golden-brown pigment. Endothelial ballooning and swelling, pavementing, denuding, scarring, and sludge formation were seen along with high endothelium in atypical locations. Dilated lymphatics were most prominent near adult worms and showed plump endothelium, thickened walls and valves, thrombus formation, and often perilymphangitis and adjacent tissue fibrosis. In vivo microscopy showed wriggling live adult worms in dilated incompetent sludge-filled groin lymphatics even when microfilaremia and peripheral edema were absent. In human tissues, in addition to "pachyderm" skin changes (keratosis, papillomatosis, acanthosis and collagen deposition), there was blood vessel and lymphatic vasculopathy similar to ferrets (angiocentric inflammation, congestion, vasculitis, thrombosis, thickened vessel walls, dilated lymphatics, lymphangitis, reactive lymph nodal hyperplasia and nodal fibrosis). These changes reflect generalized endothelial damage due to worm products, physical injury to valves and vessel walls from lymphatic-dwelling live worms, and host immune reactivity. Whereas adult worms target the lymphatic apparatus, their offspring and the host immune response primarily affects the blood microvasculature.

Endothelial cells from dilated inguinal lymphatics of congenitally athymic nude mice, parasitized by adult Brugia malayi, were placed in culture. Cells formed a loose monolayer and exhibited a typical cobblestone appearance. When microfilariae were present in cultures, they frequently appeared to be attached to the monolayer by one end. Approximately 75% of the primary explant cells were positive for Factor VIII-associated antigen, comparable to bovine artery endothelial cells used as a control. With few exceptions, cultures were uncontaminated with fibroblasts or other non-endothelial cell types. Large granular cells with characteristics of mononuclear/macrophage cells appeared in long term and unpassaged cultures. Cells remained viable in culture for an average of 60 days, 5 to 6 passages, before becoming highly vacuolated and assuming a rounded configuration. Viability of the cells was dependent upon heparin, serum and endothelial cell growth factor. The propensity of the lymphatics of nude mice to become greatly dilated in the presence of viable adult worms of B. malayi will prove to be important not only for the study of the effects of the parasite and its products upon endothelial cells, but also because a source of murine lymphatic endothelial cells can be readily available for functional studies.

Lymph thrombi in cats experimentally-infected with Brugia malayi were examined by scanning electron microscopy. A variety of morphological forms were noted and it appeared that thrombi undergo a maturation process characterized by at least three transitional phases. Initially, the thrombus consists of erythrocytes encased in fibrin (Phase I). Phase II thrombi are characterized by the appearance of phagocytic cells and fibroblasts on the surface of the thrombus. At the end of the maturation process, the thrombus surface consists solely of fibroblasts or endothelial cells, perhaps derived from the vessel wall (Phase III). Occlusion of the lymphatic lumen by thrombi and the accompanying inflammatory response triggered by B. malayi infection may be a major factor in the pathogenesis of lymph stasis in this disorder.

Domestic cats and patas monkeys were infected with Brugia malayi so that the worms localized in the regional lymphatics of the hind legs. Reaction to the filarial parasites resulted in visible local edema in cats and disruption of normal lymph flow in the monkeys. Edematous tissue was examined grossly and by light and electron microscopy. Lymph flow patterns were examined by direct observation following injection of lymph staining dye and reflection of the skin, by X-ray following injection of radio-opaque contrast media, and by lymphscintigraphy after subcutaneous injection of radioisotopes. Clinical edema occurred in cats but not in monkeys. However, disruption of normal lymph flow in monkeys infected with Brugia could be demonstrated by lymphscintigraphy.