HM Medical Clinic

Ocular Parasitic Diseases: A Review on Toxocariasis and Diffuse Unilateral Subacute Neuroretinitis Rafael T. Cortez, MD; Gema Ramirez, MD; Lucienne Collet, MD; Gian Paolo Giuliari, MD migratory behavior, and the host immunological re- Parasitic infections may damage various ocular tissues, thereby causing visual dysfunction. In 1950, Wilder de- Visceral larva migrans is characterized by gen- scribed the first case in which larval forms of nematodal eralized systemic involvement due to the migration intestinal roundworms (Ascaridoidea: Ascaris, Toxocara, capabilities of the second stage larvae of Toxocara Ancylostoma, Necator, and Strongyloides) were impli- canis. It typically presents in children from the ages cated as a cause of intraocular disease. This review fo- of 6 months to 5 years. The disease is usually self- cuses on two disorders associated with parasitic infec- limited and subclinical; however, fever, pulmonary tions: ocular toxocariasis and diffuse unilateral subacute manifestations, hepatomegaly, eosinophilia, pallor, neuroretinitis. [J Pediatr Ophthalmol Strabismus
irritability, anorexia, and malaise can occur.6,7 On the other hand, ocular toxocariasis appears in older patients, with an average age of 7.5 to 8.6 years.7-9 Several studies have revealed Toxocara and other visceral larvae migrans to be the cause of intra- Parasitic infections may produce severe dam- ocular inflammation in 9.4% of pediatric uveitis.10,11 age to various ocular tissues, thereby causing visual Rarely does a patient present with both visceral larva dysfunction. In this review, we will focus on two of migrans and ocular toxoplasmosis at the same time these infections, ocular toxocariasis and diffuse uni- or even at separate intervals.3,6,12 lateral subacute neuroretinitis (DUSN). Although these diseases are not widely distributed worldwide, Epidemiology and Life Cycle of T. canis
we believe it is of great value to the general ophthal- The adult dog usually acquires the T. canis parasite mologist to be familiar with their different presenta- by ingesting the parasite's eggs or second stage larvae tions, due to the poor visual prognosis they carry. found in contaminated soil, infected meat, and feces. The larvae form cysts and reactivation of the larvae during gestation can infect the fetal puppies in the Human infection by Toxocara, a common uterus. Following birth, the larvae migrate to the pup- roundworm that infects dogs and cats, may take one pies' lungs and then travel up the respiratory tract to of two forms: visceral larva migrans and ocular toxo- the pharynx, where they are swallowed. They then ma- cariasis.1-5 The characteristics of the infection will ture to become egg-laying adult worms in the gastroin- depend on the number of parasites, site of infection, testinal tract. Approximately 4 weeks after their birth, From Centro de Cirugía Oftalmológica (RTC, GR, LC), Caracas, Venezuela; and Princess Margaret Hospital (GPG), University of Toronto, Toronto, Ontario, Canada. Originally submitted January 4, 2010. Accepted for publication May 3, 2010.
The authors have no financial or proprietary interest in the materials presented herein. Address correspondence to Gian Paolo Giuliari, MD, 77 Elm Street, Apt. 903, Toronto, Ontario M5G H14, Canada. E-mail: [email protected]: 10.3928/01913913-20100719-02
Journal of Pediatric Ophthalmology & Strabismus • Vol. xx, No. x, 20XX
Figure . Fundus photograph montage showing Toxocara's pe-
Figure . Posterior pole Toxocara granuloma. Note a traction band
ripheral granuloma with retinal fold extending from the optic extending from the lesion to the optic disc and retinochoroidal nerve to the retinal periphery. worms begin laying eggs. Older dogs can harbor adult Several ocular presentations have been recognized, worms that do not lay eggs.13 Toxocara eggs are found the most common of which is granulomatous inflam- in the soil throughout tropical and temperate climate mation in the posterior pole or periphery.14,18-20 Some regions. In the United States and Western Europe, soil patients may present with a more marked chronic in- from parks and public areas has been found to carry a flammation in the retina and the vitreous known as contamination rate of 10% to 30%.14 In Venezuela, a 33% contamination rate was found in a metropolitan Posterior Pole Granuloma. In the acute stage,
retinochoroiditis appears clinically as a hazy, ill-de- Humans are primarily infected through the in- fined white lesion with overlaying inflammatory cells gestion of soil and food contaminated with Toxocara in the vitreous. As the acute inflammatory reaction larvae. After the eggs are ingested, they develop into subsides, the lesion appears as a well-defined elevated second stage larvae in the small intestine. They then mass ranging from one-half to four disc diameters in enter the portal circulation, following hematog- size.14,21 In some cases, traction bands may extend enous and lymphatic routes to form cysts in tissue from the lesion to the optic disc or to the macular structures.15 The parasites reach the eye through the area. In the case of chronic granulomatous inflam- retinal, ciliary, and choroidal circulation. Humans mation, large retinal vessels may infiltrate the mass are not natural hosts of Toxocara, and the parasite and disappear into its substance, probably represent- cannot mature into an adult worm in the intes- ing retinochoroidal anastomosis (Fig. 1).
Peripheral Granuloma. Ocular toxocariasis
can occur as an acute inflammatory process in the peripheral retina and ciliary body. This may either Ocular toxocariasis is typically unilateral. Pa- be preceded by mild acute inflammation in the an- tients present with unilateral decrease in visual acu- terior or posterior segment or the eye may be quiet. ity, strabismus, or leukocoria.14,16 Cases with bilateral The peripheral granuloma appears as a hazy, white, involvement are extremely rare.17 Younger children elevated mass in the peripheral fundus. It can be as- generally do not report visual changes, even if visual sociated with retinal folds that may extend from the acuity is profoundly decreased, and it is common peripheral mass to the optic nerve head or to other that parents may seek medical attention only when areas of the fundus. In some cases, the traction may the signs become striking. As such, diminished visu- lead to heterotopia of the macula, resulting in se- al acuity is frequently detected in routine examina- vere vision loss. It is likely that many cases of "con- tion.14,16 Impairment of visual acuity and leukocoria genital" retinal folds are acquired peripheral retinal are the most common presenting manifestations.
granulomas due to T. canis (Fig. 2).
Copyright SLACK Incorporated Figure . Anterior segment photograph showing leukocoria in a
patient with a cicatricial peripheral inflammatory mass and a cy-
clitic membrane in a child with ocular toxocariasis.
Figure 4. Chronic Toxocara endophthalmitis with partial retinal
Chronic Endophthalmitis. Another common
manifestation of ocular toxocariasis is chronic en-dophthalmitis (Fig. 3). This is usually associated with cyclitic membrane, retinal detachment, low that 42% of patients with presumed retinoblastoma grade anterior uveitis, and posterior synechiae. The had pseudoretinoblastoma, and 16% of these had cyclitic membrane begins to form in the peripheral ocular toxocariasis.24,25 The clinical features that quadrant of the fundus where the most severe in- may help differentiate both entities are: (1) the flammation lies and progresses across the posterior mean age at presentation for retinoblastoma is 22 surface of the lens. Severe vitritis may also manifest to 23 months, whereas for ocular toxocariasis it is as leukokoria (Fig. 4).1-5 A yellow–white mass, usu- 7.5 to 8.9 years10; (2) retinoblastoma shows tumor ally in the peripheral retina, which may resemble an growth; (3) there is a family history; and (4) there is endophytic retinoblastoma, can be seen through a lack of inflammation in retinoblastoma.14 hazy vitreous. Toxocara endophthalmitis does not Vitreoretinal traction, signs of inflammation, produce much pain or photophobia and external and posterior subcapsular cataracts may be seen in ocular examination reveals only minimal signs of in- ocular toxocariasis. However, these signs are uncom- flammation, usually with no ciliary flush. Hypopy- mon in patients with retinoblastoma. Computed on may develop in severe cases.16 A cicatricial stage tomography and B-scan ultrasonography may show is characterized by tractional bands that may pull the typical tumor pattern in patients with retino- on the retina and ciliary body. Patients with endo- blastoma, with evidence of calcification within the phthalmitis are usually younger than patients with mass.26 On the other hand, endophthalmitis sec- posterior pole granuloma.
ondary to toxocariasis does not commonly demon- Atypical Presentation. Optic nerve granuloma,
strate a tumor pattern.14 papillitis, inflammatory iridial mass, intracorneal Additionally, ocular toxocariasis may present larvae, motile larvae in the vitreous and retina, and with eosinophils in the vitreous or aqueous humor scleritis may occur.2,19,22,23 We evaluated two cases without evidence of malignant cells on histopatho- that presented with vitreous hemorrhage; after the logic examination. This may be observed in the hemorrhage cleared up, the typical fundus changes presence of normal levels of lactate dehydrogenase of a posterior pole granuloma were detected.
and phosphoglucose isomerase. Other entities to be excluded are toxoplasmic retinochoroiditis, pars pla- nitis, retinopathy of prematurity, familial exudative Toxocara endophthalmitis may closely resemble vitreoretinopathy, persistent fetal vasculature, Coats' an endophytic retinoblastoma. Shields et al. found disease, and organized vitreous hemorrhage.14 Journal of Pediatric Ophthalmology & Strabismus • Vol. xx, No. x, 20XX
dicate that this is not the case.20,30-32 The ultimate The current gold standard to test for systemic or utility of antihelmintic therapy remains equivocal. ocular infection with T. canis is the enzyme-linked Surgical Treatment. Surgery is reserved for
immunosorbent assay (ELISA), which carries both post-inflammatory complications such as persis- a sensitivity and specificity rate of approximately tent vitreous opacification, retinal detachment, and 90%.14 Although the Centers for Disease Control epiretinal membrane formation with vitreomacular and Prevention considers serum ELISA titers of less or optic nerve traction (Fig. 5).The most common than 1:32 to be insignificant for the diagnosis of indication for surgical intervention in ocular toxo- systemic toxocariasis, other institutions have stated cariasis is retinal detachment.27,30,31,33 Retinal reat- that a serum titer of 1:8, or even lower, is sufficient tachment has been performed in 71% to 88% of to support the diagnosis if the patient has signs and ocular toxocariasis cases, with visual improvement symptoms compatible with the disease.14,18,27 How- in most patients.27,30,31,33 ever, a positive serum titer cannot be used to defini-tively confirm the diagnosis of ocular toxocariasis, DIFFUSE UNILATERAL SUBACUTE
although the absence of serologic evidence of Toxo- cara presence could reduce the odds of this organ- DUSN was first described by Gass et al.34 and ism being the cause of ocular disease.14,18 Authors Gass and Scelfo35 in 1978. They described 29 patients have found that 31.8% of affected children without between the ages of 5 and 22 years with severe visual signs of ocular toxocariasis exhibited a serum titer loss in one eye, vitritis, mild papillitis, and recurrent of 1:16 or greater.14,18 ELISA testing of intraocular crops of evanescent, gray–white lesions affecting the fluids has been demonstrated to be of great value in outer retina and pigment epithelium. These lesions diagnosing ocular toxocariasis.10,14,18,19,28 are usually followed by progressive loss of visual field, optic atrophy, narrowing of the major retinal vessels, diffuse and focal depigmentation of retinal pigment The treatment of ocular toxocariasis depends pri- epithelium throughout the fundus, and a moderate to marily on the extent of inflammation at presentation marked reduction of the b-wave amplitude on mul- and the secondary structural changes in the vitreous tifocal electroretinogram. Previously, this condition and retina that are associated with the disease.14 In was termed "unilateral wipe-out syndrome."34,35 most cases of severe nematode endophthalmitis, nu- DUSN is most prevalent in the southeastern merous complications ensue that frequently result in United States and the Caribbean, although some total blindness in the involved eye. Therefore, prompt cases have been reported in many sections of the treatment is justified in such cases.14 United States, Canada, the northern part of South Medical Treatment. With ocular toxocariasis,
America, Europe, and China.36-41 the objective of treatment is to reduce inflamma- In the United States, DUSN is probably caused tion to prevent the formation of membranes that by at least two different nematodes. The smaller can consequently affect intraocular structures. one, Ancylostoma caninum, measures between 400 Periocular and systemic steroids (0.5 to 1 mg/kg and 1,000 µm in length and has a diameter of ap- prednisone daily) are the mainstays of therapy for proximately one-twentieth of its length.36-39 It is eyes with active vitritis. Cycloplegic agents should mainly found in the southeastern United States, the be employed when signs of anterior segment in- Caribbean, and the northern part of South Amer- volvement are present.14 There have been reports of ica.36-39 A larger nematode, Baylisascaris procyonis, clinical improvements of ocular toxocariasis treated 1,500 to 2,000 µm long, is responsible for DUSN in with antihelmintic agents thiabendazole (25 mg/kg the northern-midwestern United States and in some twice daily for 5 days with a maximum of 3 g per parts of Brazil.34,38,42,43 day), albendazole (800 mg twice daily for 6 days), or mebendazole (100 to 200 mg twice daily for 5 days).14,29 Although it has been proposed that an- Ocular findings in DUSN have been well de- tihelmintic treatment may initiate an intraocular scribed by Gass et al.34-39 Most patients are young inflammation due to a hypersensitivity response to and healthy, with ages ranging from 11 to 65 years dead larvae, clinical and experimental evidence in- (the mean age being 24 years) at the time of the ini- Copyright SLACK Incorporated Figure . (A) Toxocara peripheral granuloma with traction fibrotic band extending to the optic nerve. (B) Fundus photograph of the same
patient 6 weeks after pars plana vitrectomy.
early stages, inflammation in the anterior segment is uncommon, although keratic precipitates and hypopyon were observed and reported in one pa-tient.34,35 Visual acuity may be reduced moderately if the condition is detected early, but it is usually markedly decreased at the time of presentation. The fundus changes, which are the most promi-nent feature of this syndrome, have been divided into early and late.34,35 The onset of DUSN is subtle and progres- sive.34,35 Patients in the early stages of the disease may present with low vision in the affected eye, mild to moderate vitritis, optic disc swelling, and recur-rent crops of evanescent, multifocal, gray–white le- Figure 6. Early stage of diffuse unilateral subacute neuroretinitis.
Note the vitritis, optic disc swelling, and crops of multifocal gray–
sions at the level of the outer retina (Fig. 6). The white lesions.
lesions are typically clustered in one segment of the fundus, and successive crops of these lesions may re-cur in close proximity to previously affected areas. tial presentation.39 For the most part, it is a unilat- The nematode, which often assumes an S-shape eral condition; although uncommon, bilateral cases or coiled position, should be sought out in the vicin- have been described.37,39,40 ity of the active lesions. In the absence of these white Many patients, particularly children, may be lesions, no other markers exist for the location of the asymptomatic and visual loss is usually discovered worm. Nematodes propel themselves by a series of on routine eye examination. Other patients may slow coiling and uncoiling movements, or by slith- present with acute onset of multiple, and rapidly ering, snake-like movements. The examining light changing, central or paracentral scotomata, pho- seems to stimulate movement in the nematode and topsias, or unilateral vision loss.34,35,44-46 In the causes it to move deeper into the subretinal space Journal of Pediatric Ophthalmology & Strabismus • Vol. xx, No. x, 20XX
was 20/400 or worse in 69 patients (84.1%). Ad-ditionally, a subretinal nematode was identified in 33 eyes (40.2%). All of the nematodes were small, measuring approximately 400 µm in length.
As mentioned, patients with DUSN suffer pro- gressive vision loss and seek medical attention in the late stages of the disease. Consequently, the clinician should focus on the early recognition of this syn-drome because treatment may prevent further dete-rioration of visual function and may even result in visual improvement.34,35 In patients with suspected Figure 7. Late stage of diffuse unilateral subacute neuroretinitis.
DUSN, we first suggest an evaluation using indirect Diffuse and focal changes of the retinal pigment epithelium. Nar- ophthalmoscopy with a 20-diopter lens (or in some rowing of the retinal arterioles and mild pallor of the optic nerve. cases a 14-diopter lens) to locate the crops of evanes- Note the intraretinal parasite superior to the fovea.
cent white lesions and to attempt to locate the nema-tode around these areas. Subsequent biomicroscopy where the clinician may lose the opportunity to in that area with a 78-diopter lens allows the exam- identify it. In such cases, the light stimulus should iner to definitely identify the nematode.34,36 In the be discontinued for the organism to reemerge from absence of white lesions, a careful biomicroscopic the deeper structures.34-36,43,47 search of the entire fundus is necessary to find the Occasionally, perivenous retinal exudation and worm, and multiple patient visits may be required. sheathing may be observed. In addition, cystoid It is also possible to identify the parasite by careful macular edema, intraretinal and subretinal hemor- examination of fundus photographs that include the rhages, retinal exudation, and neovascularization suspicious areas. may present during the early stages of the disease.34 Fluorescein angiography is not helpful in locat- Over a period of weeks to months, late manifesta- ing the nematode.36 Scanning laser ophthalmoscopy tions begin to appear.36 Diffuse and focal depigmen- using a blue light can help locate the worm due to tation of the retinal pigment epithelium is seen. This the provided advantage of enhancing contrast, im- is usually less prominent in the central area. Gradual proving visualization, and recording a videography narrowing of the retinal vessels and an increase in of the worms' movements.48 pallor of the optic disc will frequently result in an Multifocal electroretinogram is subnormal in afferent pupillary defect (Fig. 7). In general, the de- the affected eye during all stages of the disease, with gree of optic disc pallor and retinal vessel narrow- b-wave being more affected than a-wave.36 Serologic ing parallel that of central visual loss, but striking studies, stool examination, and peripheral blood exceptions do occur.34,35 Fluorescein angiography smears are of little value in diagnosing DUSN.10,37 will reveal hypofluorescent lesions that turn hyper- Toxocara and B. procyonis antibody titers have been fluorescent in the late stages of the test. Dye leak- proposed as diagnostic tools to try to identify the age occurs at the optic nerve level; active lesions and disease.49 No serologic test is currently available for petaloid hyperfluorescence are observed in cases of Ancylostoma caninum. Because of the possibility of cystoid macular edema. In more advanced stages of commonly shared antigens by different nematodes the disease, fluorescein angiography may reveal mul- or seropositivity unrelated to the actual infecting tiple hyperfluorescent lesions due to window defects nematode, interpretation of serologic testing may be secondary to retinal pigment epithelium alterations subject to error.48 together with a delay in retinal circulation time.35 The clinical evaluation of 78 patients in Ven- Etiology and Pathogenesis
ezuela39 showed the typical funduscopic late chang- There is no consensus regarding the identifica- es described by Gass et al.36 The mean age of these tion of the subretinal nematode frequently found in patients was 16.7 years; the presenting visual acuity DUSN. Reports suggest B. procyonis, A. caninum, Copyright SLACK Incorporated Figure 8. (A) Late stage of diffuse unilateral subacute neuroretinitis. Note the parasite around the retinal vessel (arrow). (B) Fundus photo-
graph of the same patient after retinal photocoagulation of the parasite.
Dirofilaria, and a larval form of T. canis as possible is caused by products left in the worm's wake, and a infectious agents involved in DUSN.50 However, more diffuse toxic reaction affecting both the inner the larval form of T. canis is smaller than the worm and outer retinal tissues ensues.36 Histopathologic that causes DUSN and there is a lack of serologic study of an eye believed to be affected by DUSN evidence to support the mentioned reports. In addi- revealed nongranulomatous vitritis and retinitis. It tion, funduscopic manifestations are different than also showed retinal and optic nerve perivasculitis, those associated with other forms of ocular toxoca- extensive degeneration of the posterior retina, mild riasis and the high prevalence of T. canis does not optic atrophy, mild degenerative changes in the reti- correlate with the scant number of DUSN cases re- nal pigment epithelium, and a low-grade, patchy, non-granulomatous choroiditis.34,35 A. caninum, which is a common nematode para- site that infects dogs, is suspected of causing DUSN because it frequently results in cutaneous larval mi- The condition most likely to be mistaken for grans that may later manifest signs of DUSN. The DUSN is multiple evanescent white-dot syndrome worm can survive for months and even years with- (MEWDS), although in the early stages DUSN out changing form and its infective larva measures may resemble toxoplasmosis, cytomegalovirus, and approximately 650 µm. This better corresponds to bacterial abscesses. MEWDS can be distinguished the entity described in DUSN.34,35 Scanning elec- from DUSN by an accompanying history of flu-like tron microscopy of a nematode excised from a case symptoms, photophobia, wreath-like hyperfluores- of DUSN by means of an eye wall biopsy was com- cent dots on fluorescein angiography, blind spot patible with, but not diagnostic for, A. caninum. enlargement, multiple gray or whitish outer retinal B. procyonis is an intestinal nematode that in- lesions, and decreased electroretinogram record- fects raccoons and skunks. The larva measures be- ings.51,52 Visual acuity may even return to normal tween 300 and 2,000 µm, and it has been proposed levels in some cases after several weeks or months. as the larger nematode responsible for DUSN.49,50 On fluorescein angiography, the white lesions in Nevertheless, infrequent exposure to raccoons or DUSN block the fluorescence in the early phase, skunks and the absence of central nervous system whereas in MEWDS the lesions are hyperfluores- involvement make B. procyonis a highly unlikely cent in the early stages of the angiogram. Rarely, one pathogen in DUSN. can mistake DUSN for sarcoidosis, presumed ocular The pathogenesis of DUSN appears to involve histoplasmosis syndrome, and multifocal choroidi- a mechanical, inflammatory, and toxic assault on the tis due to the appearance of focal chorioretinal scars outer retina. A local toxic effect in the outer retina scattered throughout the fundus.53 The absence of Journal of Pediatric Ophthalmology & Strabismus • Vol. xx, No. x, 20XX
optic atrophy, vitritis, vessel attenuation, and the presence of normal-looking retinal pigment epithe- Ocular toxocariasis and DUSN may produce se- lium between punched out lesions is more likely to vere damage to the intraocular structures, causing sig- be encountered in DUSN. Eyes with central retinal nificant visual impairment. Although these diseases artery occlusion may show some characteristics that are not well distributed worldwide due to their poor look like DUSN. Also, the late stages of DUSN may visual prognosis, it is of great importance that physi- be confused with retinitis pigmentosa, secondary cians be aware of the variety of clinical forms in an bone-spicules migration, and posterior subcapsular effort to achieve an early diagnosis and treatment. opacification, but unilaterality is characteristically a feature of DUSN.34,35 Trauma may exhibit some DUSN characteristics such as retinal pigment epi- 1. Beaver PC, Snyder CH, Carrera GM, Dent JH, Lafferty JW. Chronic eosinophilia due to visceral larva migrans; report of three thelial changes and optic atrophy.34,35 cases. Pediatrics. 1952;9:7-19.
2. Baldone JA, Clark WB, Jung RC. Nematode ophthalmitis: report of two cases. Am J Ophthalmol. 1964;57:763-766.
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4. Gillespie SH. Cutaneous larva migrans. Curr Infect Dis Rep. laser application, is the treatment of choice36,43,47 (Fig. 8), although visual acuity does not significantly 5. Wilder HC. Nematode endophthalmitis. Trans Am Acad Ophthal- mol Otolaryngol. 1950;55:99-109.
improve unless the worm is killed soon after onset 6. Huntley CC, Costas MC, Lyerly A. Visceral larva migrans syn- of visual loss.54,55 Photocoagulation does not cause drome: clinical characteristics and immunologic studies in 51 pa-tients. Pediatrics. 1965;36:523-536.
exacerbation of inflammation and results in prompt 7. Schantz PM, Glickman LT. Toxocaral visceral larva migrans. N and permanent inactivation of the disease; however, Engl J Med. 1978;298:436-439.
the search for the nematode can become a time-con- 8. Schantz PM, Stehr-Green JK. Toxocaral larva migrans. J Am Vet Med Assoc. 1988;192:28-32.
suming and frustrating task.36,43,47 9. Schantz PM, Weis PE, Pollard ZF, White MC. Risk factors for Several oral antihelmintic medications, such toxocaral ocular larva migrans: a case-control study. Am J Public as thiabendazole and dietylcarbavazine, have been 10. Schantz PM, Meyer D, Glickman LT. Clinical, serologic, and epi- used in an effort to treat this disease.36,56,57 However, demiologic characteristics of ocular toxocariasis. Am J Trop Med most of the studies reported that only the subretinal 11. Benezra D, Cohen E, Maftzir G. Patterns of intraocular inflam- worms were killed, probably due to inadequate ocu- mation in children. Bull Soc Belge Ophtalmol. 2001;279:35-38.
12. Paul M, Stefaniak J, Twardosz-Pawlik H, Pecold K. The co-occur- lar penetration of the drugs. Hence, it has been sug- rence of Toxocara ocular and visceral larva migrans syndrome: a gested that if the worm cannot be found in a patient case series. Cases J. 2009;2:6881.
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Harvard Journal of Law & Technology Volume 24, Number 2 Spring 2011 REVERSE SETTLEMENTS AS PATENT INVALIDITY SIGNALS Gregory Dolin, M.D.* TABLE OF CONTENTS I. INTRODUCTION .282 II. THE HATCH-WAXMAN ACT .286 A. The Structure and Purposes of the Act . 286 B. The Mechanics of the Hatch-Waxman Act. 290 III. REVERSE SETTLEMENTS .293

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