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Retinopathy in Generalized Loa-Loa

A Clinicopathological Study

D. TOUSSAINT, MO, and P. DANIS, MD, Brussels

Introduction : anterior chamber,*'^''­" retinal hemorrhages,* Filarias Pathogenic to Man or the présence of microfilariae in the lacrymal gland's sécrétion. The filaria is a parasite which belongs to the group of . Four types are In filariasis, the adult maie worm pathogenic to man: , has a length of 1.5 cm to 3 cm, while the causing Bancroft's filariasis; Onchocerca female has a length of 3 to 6 cm. Both the volvulus, causing ; Loa loa, adult maie and female have a diameter of causing loaiasis; and Dracunculus medinen- 400 m/x. The adult worm lives in the sub­ sis, causing . Thèse infections cutaneous tissues where it continuously are transmitted by insects which harbor migrâtes. It becomes visible where the skin larvae. Thèse larvae inoculated in man is very thin (eyelids, bulbar and palpebral libéra te microfilariae, some of which are conjunctivae) and provokes a transient blood­borne ( W bancrofti and L loa), while edema of the subcutaneous tissues (Calabar others remain in the subcutaneous tissues swellings). The incubation period is from (O volvulus and D medinensis). 3 to 12 months and the parasite may survive from 17 to 20 years. The microfilariae have In D filariasis, the only ocular complica­ a diameter of 7 m/x and a length of 275 m/x tion seems to be the localization and eventual and invade the peripheral blood stream calcification of a filaria behind the eye­ball. during the day. A filarial inoculation is ac­ Onchocerciasis (O volvulus) is seen in companied by and rise in blood Central Africa and in Central America. Its albumin, but is usually considered benign as ocular pathogenic rôle is much more fré­ far as the eye is concerned. quent than that of the other filariae. Thèse four filarias pathogenic to man Onchocerciasis may manifest itself by: have in common the ability to create a state keratitis, conjunctivitis, iridocyclitis, chorio­ of sensitization and allergy.^" Although the retinitis, and atrophy of the optic nerve. The ocular pathological rôle oi L loa was previ­ last two resuit from filarial arteritis.^"*'"'!® ously considered limited, the several descrip­ Bancroft's filariasis (W bancrofti) is seen tions of meningoencephahtis i.6.7,i3,i5,i9 force principally in Australia. From the ophthal­ us to reconsider the possibility of ocular in­ mological point of view, it may be manifest volvement. The spontaneous lysis of blood­ by: elephantiasis of the eyelids, iritis caused borne microfilariae causes a sensitization of by the présence of an adult worm in the the which is repeated by each new de­ Submitted for publication Oct 16, 1965. struction of microfilariae. During the course Read before tlie third meeting of the European Ophthalmic Pathology Society (Vienna, June 1964). of loaiasis the présence of cardiopathies, From the University of Brussels; Department of Ophthal- clinically similar to Lôffler's endocarditis, mology (Dr. P. Danis) ; Department of Internai Medicine (Dr. P. Bastenie); Department of Pathology (Dr. P. and of nephropathies, some apparently al­ Dustin). Reprint requests to Service anatomie pathologique, Fonda­ lergie and some having histological aspects tion Médicale Reine Elisabeth, Institut de Recherches, 1, Avenue J.­J. Crocq, Bruxelles 9, Belgique (Dr. Toussaint). similar to periarteritis nodosal involvement Arch Ophthal— Vol 74, Oct 1965 RETINOPATHY IN LOA-LOA FILARIASIS—TOUSSAINT & DANIS 471 of the kidney, suggests a similarity between In addition to its rarity, interest in the the symptomatology of filariasis and that of présent case résides in the possibility of ob- the collagen diseases or allergie reactions. It serving the reaction of the retinal vessels is now accepted that neurological accidents towards intravascular foreign bodies of are of an allergie nature and that chemo- known dimensions. The foreign bodies, be- therapy may provoke aeute allergie accidents eause of their number and size, create a by the sudden libération of a large quantity disturbance of the retinal circulation that of allergen. It is supposed that loaiasis takes has not yet been obtained experimentally. the form of a serions multiviseeral affection only in the rare cases where the allergen de- Report of Case * velops in a particularly réceptive host.-'^ A. Clinical Observation.—The patient was a 38- Infiltrations of L loa have been observed year-old white maie, who at the tinie of his admission on Mardi 16, 1963 was somnolent and ob- in the venous System of the central nervous tunded. He présentée! bilatéral réduction of vision System, the heart, the spleen, and the rénal with photophobia, increase in the size of the parot- glomeruli, but to date there has been no ids, discrète petechiae disseminated over the whole mention of this type of involvement in the body, and mobile in the left upper lid. retinal vessels. The only account of a reti- The affection had started three weeks previously as a grip with a température of 38 C (100.4 F), nal vascular involvement by L loa filariae asthenia, and generalized stiffness but without head- was published by Langlois et al.^" They re- aches or vomiting. The Personal antécédents re- ported the case of a 44-year-old maie, af- vealed malaria in 1952 during a stay in the Congo flieted with filariasis for several years, who (treated with chloroquine [Nivaquine]) and loai• asis which manifested itself by a vague pruritus, suddenly developed an obstruction of the local cdema, and rare épisodes of albuminuria. No central retinal artery in the right eye. The spécifie treatment had been instituted. absence of histologie confirmation might provoke question of the filarial origin of the * For further détails refer to Gauchie, C, et al: Un cas de méningite filarienne à Loa-loa, Belge Path Med Exp, to thrombosis. be published.

Fig 1.—Hemorrhagic area in the nerve flber lay- lumen of the capillary eut longitudinally (PAS- er. On the left, five microfilariae in the lumen of hematoxylin). a vessel eut transversely. Two microfilariae in the

Arch Ophthal—Vol 74, Cet 1965 472 RETINOPATHY IN LOA-LOA FILARIASIS—TOUSSAINT & DANIS

Fig 2.—Extensive se- rous infiltration of the nerve fiber layer and the outer plexiform layer. Corkscrew appearance of the MûUer's fibers. Free microfilariae in the se• rons material. Celloidin embedding (PAS-hema• toxylin) .

The ocular examination revealed large superficial The complément fixation test with antigen pre- hemorrhagic sheets of variable forms in the retina pared from the L ha filariae was positive in the (some more or less round, others triangular with sérum and négative in the spinal fluid (Prof Van a peripheral base). The lésions were disseminated Breuseghem). A skin of the crural région between the optic dise and the equatorial retina revealed the présence of numerous filariae. and alternated with, or were covered by, zones of Evolution : During the first five days of hospital- yellowish exudate. There were also a few whitish ization the mental state of the patient improved filaments simulating obstructed arterioles. An ex• without any treatment while the visual acuity pro- ploration of the visual acuity was impossible due gressively declined. The installation of a meningo- to the lack of coopération from the patient. encephalitic syndrome attributed to the filariasis The various laboratory tests were normal except and the worsening of the retinal lésions justified a for the blood sédimentation rate (60 mm/hour) treatment with filaricides ( and the spinal fluid (albumin: 110 to 120 mg%, [Hetrazan]) in increasing doses: one-fourth tablet présence of white blood cells : 30 to 100 eu mm, twice the first day ; one-half tablet twice the second présence of microfilariae). The absence of eosin- day ; one tablet twice the third day ; four tablets ophilia, the normal blood platelet count, and the four times on the fourth day. This treatment was CSF glucose of 72 mg% are worth emphasizing. started under the cover of antihistaminic drugs

Fig 3.—Retinal vessel containing numerous microfilariae (PAS-hematoxylin).

Arch Ophthal—Vol 74, Oct 1965 RETINOPATHY IN LOA-LOA FILARIASIS—TOUSSAINT & DANIS 473

lariae were found in the whole body. The showed important lésions of bronchopneumonia and numerous vascular thromboses. The liver showed venous stasis and the spleen was fibrotic. There was extensive sclerosis of the kidneys with calcium oxalate crystals in the excretory canal. The cérébral cortex and the white substance of the brain showed numerous lésions centered around the vessels. Some of the capillaries were ob- structed by microfilariae and surrounded by pe- techiae. In the white substance of the brain, one of thèse lésions showed a with multinu- cleatetl giant cells of the "foreign body" type, three or four of thèse cells being grouped in a small nodule. Similar nodules, but made up of mono- nucleated histiocytes, were found at other sites. Some of thèse nodules contained extravascular microfilariae. At other sites, there were récent lésions of the neurones characterized by bright eosinophilic cytoplasm and pyknotic, shrivelled nu- clei adjacent to normal cells. Thèse cell lésions were not consécutive to postmortem autolysis but to ischemia. In addition, the gray substance of the Fig 4.—Sheath of lymphocytes around a venule in the nerve fiber layer (PAS-hematoxylin). brain contained round eosinophilic masses of un- known nature, differing from amyloid bodies. The and cortisone. On the fourth day the patient became vessels near the nuclei of the brain showed poly- nuclear infiltration. The subarachnoid spaces con• comatose and died on the seventh day. It is likely tained microfilariae. that the aggravation of the patient's condition is attributable, despite the précautions, to allergie C. Ocular Pathological Examination.—Tech• phenomena consécutive to the treatment by filari- niques : One eyeball was fixed in 10% Formalin, the other in Bouin's fluid. A portion of the lower cides. It is, however, évident that the progress of and upper part of each eye was removed. Thèse the retinal lésions and the neurological symptoms four latéral portions were submitted to trypsinic indicated a dissémination in the nervous System digestion or embedded in paraffin after being flat- and the need for an effective treatment. tened and eut tangentially." Of the two médian B. General and Neuropathological Examination.'\ portions containing the optic nerve, one was em• A large quantity of adult filariae was présent in bedded in paraffin, the other in celloidin, and both the dermis and the epidermis. Numerous microfi- were sectioned in the usual manner. Stains were

t J. Rutsaart, MD, and O. Périer, MD. Iiematoxylin and eosin, Masson's trichrome, Mac-

Fig 5.—Trypsinic di• gestion, unstained vessels observed in phase con- trast. Five microfilariae in the lumen of the cap• illaries. One of the ends of both microfilariae 2 and 5 are outside the field. The pericytes are normal.

Arch Ophthal—Vol 74, Oct 1965 474 RETINOPATHY IN LOA-LOA FILARIASIS—TOUSSAINT & DANIS

Fig 6.—Twenty micro- lllariae in the lumen of the capillaries. The arrows indicate the two ends of the microfilariae. The pericytes are nor• mal (trypsinic digestion; l'AS-liematoxylin).

Manus-Hotchkiss periodic acid, and Gram-Weigert. and the outer plexiform layer (Fig 1). The Cross Sections : Both retinae presented exten- hemorrhagic areas are located under the limitans sive lésions going from the equator to the optic interna. In other places they infiltrated ail the disk. In several areas the thickness of the retina is retinal layers. The infiltration of the stratum quintuplicated owing to extensive hemorrhagic opticuni and the outer plexiform layer gives a cork- sheets or serons infiltration of the stratum opticuni screw appearance to MûUer's fibers. The serous ma-

Fig 7.—Black Unes, 250 m/i long, in the lumen of disappearance of the pericytes (trypsinic digestion; the vessels are microfilariae. Main vessels are en- hematoxylin and eosin). sheathed with lymphocytes. Microaneurysms and

Arch Ophthal—Vol 74. Oct 1965 RETINOPATHY I.W LOA-LOA FILARIASIS—TOUSSAINT & DANIS 475

Fig 8.—Three microfi- lariae in the lumen of the vessels. Microaneurysms and disappearance of the pericytes. Black dots in the lumen of the capil- laries are lymphocytes, monocytes, and cells hav- ing phagocyted pigmented material from destroyed microfilariae (trj'psinic di• gestion ; hematoxylin and eosin).

terial contains occasional free microfilariae. The less of the caliber of the vessel. On the other hand, ganglion cells completely disappeared at the site the distal third of the fragments contains a large of the serohemorrhagic infiltration. Thcre is a cer• number of microaneurysms having the form of a tain relation between the amount of retinal edema latéral excrescence of the capillary wall. They are and the présence of free microfilariae. At the pos- of variable size and have the aspect of the latéral terior pôle, the retina is separated from the pig- or saccular type of aneurysms. The walls are of mentary epithelium by a serous material containing normal thickness. The most fréquent appearance is also a few microfilariae (Fig 2). The lumen of a that of a string of beads, but some aneurysms are large number of vessels contains microfilariae whose completely isolated. There is complète disappearance cuticles are easily recognizable. In the capillaries the of pericytes, both below and above the sites of the microfilariae are in single file, whereas in the larger aneurysms. In contrast, there is a variable behavior vessels they are side by side, with a maximum num• of the endothelial cells ; absence in certain areas ber of six abreast (Fig 3). Some of the large vessels, whcre aneurysms are présent, prolifération in other mainly veins, are ensheathed with lymphocytes (Fig areas. The microaneurysms are less well difïeren- 4). The choroidal vessels contain rare microfilariae. tiated in the area where the endothelium is still The choroid itself shows only a few agglomérations présent than in the area where it has disappeared. of lymphocytes. The ciliary body, the iris, and the The lumen of some microaneurysms are totally optic nerve are normal. or partially occupied by coiled microfilariae. Retinal Digestion : Four retinal fragments of tri- There is no apparent relationship between the angular form, situated 2 mm from the optic dise présence of intracapillary microfilariae and the dis• with the base corresponding to the equator, were tribution of the microaneurysms. submitted to a trypsinic digestion (Fig 5, 6, 7, 8). Thèse préparations show intravascular microfi• Comment lariae both in the priraary branches of the central vessels and in the peripheral capillaries. On the The histological aspect of this case is whole, a quarter of the vascular network is occu- unique and striking because of the abun- pied by microfilariae. The density of microfilariae in dance of intravascular as well as extra- a vascular unit (group of capillaries fed by an vascular microfilariae, the extent of the arteriole or drained by a venule) is irrcgular from exudative and hemorrhagic processes, and one unit to another. The distribution of microfilariae does not seem to be conditioned by anatomical or the vascular reaction of lymphocytic type. mechanical factors. The lumen of the vessels con• The aneurysmal dilatations of the capil• tain only a few cells : some lymphocytes, mono• laries remaind one of those reported by Ash- cytes, and some cells which have pliagocyted pig• ton ° in a case of macroglobulinemia of mented material from destroyed microfilariae. The Waldenstrom: the same "string of beads" microfilariae have not altered the cell structure in the internai proximal two thirds of thèse triangular aspect but more peripheral than in diabetic retinal fragments. The endothelium and the peri• retinopathy. Generally speaking the acellular cytes have a completely normal appearance, regard- microaneurysms seem to be found in the Arch Ophthal—Vol 74, Oct 1965 476 RETINOPATHY IN LOA-LOA FILARIASIS—TOUSSAINT & DANIS more peripheral retinal territories than those régions in the inner nuclear and outer plexi- where the microaneurysms with endothelial form layers; retinal albuminous exudation prolifération are found. (outer plexiform layer); intra- and subreti- It should be noted that completely normal nal free microfilariae; lymphotic ensheath- retinal vessels could be found in territories ing of some of the main vessels (veins). which were destroyed by microcystic degen- The présent study was supportée! by grants from the National Institute of Arthritis and Metabolic Diseases (NIH eration. The absence of supporting frame- Research Grant: AM064990-03 PTHA) the Fonds de la Recherche Médicale Scientifique (445) and the National work of the retina does not seem to have Council to Combat Blindness Inc. (Post-doctorat Fellow- influenced the caliber of the vessels. ship 168).

The présence of microfilariae does not REFERENCES bring about any modifications of the caliber 1. Alajouanine, T., et al: Encéphalite après endocardite of the vessels. Nothing suggests the prés• fibroplastique d'origine filarienne, Rev Neurol 101:656, 1959. 2. Appclmans, M.: Les troubles visuels dans l'onchocer- ence of blood stasis above the agglomération cose africaine, Rev Belge Soc Méd 7:525, 1935. of microfilariae. The distribution of the mi• 3. Appelmans, M. : L'onchercercose africaine maladie paradoxale, Bull Mém Soc Franc Ophtal 71:244, 1958. crofilariae indicates that they circulate f reely 4. Appelmans, M.: Diagnostic et traitement de l'oncho- cercose, Paris: Masson et Cie, Soc Franc Ophtal, 1948. in the vascular network and are not carried 5. Ashton, N.; Kok, D'A.; and Foulds, W.S.: Ocular passively by the blood stream. Pathology in Macroglobulinaemia, / Path Bact 86:453, 1963. 6. Bertrand-Fontaine, J., et al; Un cas de filariose céré• brale (double hémiplégie au cours d'une filariose à Loa-Loa). Bull Mém Soc Méd Hôp 64:1092, 1948. Summary 7. Bonnet, R. : Réflexions sur un cas de méningite aiguë à microfilaire Loa, Méd Trop 4:273, 1943. The présent paper reports a clinicopatho- 8. Coppez, H. : Un cas de filaire dans la chambre antérieure de l'oeil, Arch Ophtal 14:559, 1894. logical study of generalized loaiasis with 9. EUiot, R.H. : Ophtalmologie tropicale, Paris: Masson meningoencephalitis and ocular involvement. et Cie, 1922. 10. Gentilinî, M. : Les filarioses Pathogènes de l'homme, A mobile filaria was présent in the subcu- Paris: Arnette, 1962. 11. Hissette, J. : Mémoire sur l' taneous tissue of the left eyelid. Ophthal- Leuckaert et sur les manifestations oculaires au Congo belge, moscopic examination showed superficial Ann Soc Belge Méd Trop 12:435, 1932. 12. Janssens, P.G., et al: Réflexions sur le sort des mîcro- hemorrhagic sheets and yellow exudative filaires de Loa-Loa dans l'organisme humain parasité. Mani• festations viscérales provoquées par leur infiltration dans areas around the optic disk and the macula. les tissus, Bull Soc Path Exot 51:632, 1958. The retina was not raised and the vessels 13. Kivitz, M.: Quatre cas d'encéphalite mortelle avec invasion du liquide céphalo-rachidien par microfilaire Loa, had a normal appearance. Ann Soc Belge Méd Trop 32:235, 1952. 14. Kuwabara, T., and Cogan, D.G.: Studies of Retinal Histological examination (trypsinic di• Vascular Patterns. I. Normal Architecture, Arch Ophthal gestion of the retina, tangential and per- 64:904, 1960. 15. Langlois, M., et al: Filariose Loa, Thrombose de l'• pendicular sectioning after embedding in artère centrale de la rétine et syndrome cérébelleux, Rev Neurol 107:381, 1962. paraffin) revealed the présence of a large 16. Ochoterena, I.: Contribution para el conocimiento de number of intravascular filariae in the ret• la onchocercisis en Mexico, Ann Instit Bwl Mexico 1:307, and 2:109, 1931. ina, rare filariae in the choroidal vessels; 17. Tawara, M. (Fukuoka) : Une filaire dans la chambre aneurysmal dilatation of the peripheral reti• antérieure d'un japonais, Acta Soc Ophthal Jap 40:518, 1936. 18. Toussaint, D. : Etude histologique sur coupes sériées nal capillaries ("string of beads" appear• de rétines diabétiques mises a plat (méthode personnelle), ance) ; extensive retinal hemorrhages Bull Soc Belge Ophtal 123:530, 1959. 19. Van Bogaert. L.. et al: Encephalitis in Loa-Loa principally in the layers of the optic fibers Filariasis, / Neurol Ncurosurg Psychiat 18:103, 1955. 20. Wright. J. : Adult Filaria Wuchereria Bancrofti in and of the ganglion cells, extending in some the Anterior Chamber, Brit J Ophthal 18:646, 1934.

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