Educational Workshop EW08: Management of Ocular Parasitic Diseases

Home , Cysticercosis, Dirofilariasis, Dirofilaria repens, Loa loa, Parascaris equorum

Educational Workshop EW08: Management of ocular parasitic diseases

Arranged with the ESCMID Study Group for Clinical Parasitology (ESGCP)

Convenors: Birgitta Evenbard (Umea, SE) Carmen-Michaela Cretu (Bucharest, RO)

Faculty: Francisco Arnalich (Madrid, Spain) Carmen-Michaela Cretu (Bucharest, Romania) Hélène Yera (Paris, France) Peter Chiodini (London, United Kingdom) - no handout available

2 Arnalich - Ocular acanthamoebiasis

Ocular Acanthamoebiasis

Dr. FRANCISCO ARNALICH

CORNEA UNIT- OPHTHALMOLOGY SERVICE HOSPITAL UNIVERSITARIO RAMÓN Y CAJAL DE MADRID, SPAIN

“WITHOUT CLINICAL AWARENESS AND THEREFORE PROMPT DIAGNOSIS AND TREATMENT IT CAUSES BLINDNESS”

• Mainly a primary corneal disease which can extend to: • Sclera • Anterior chamber • Iris • Vitreous chamber • Retina

3 Arnalich - Ocular acanthamoebiasis

• Contact Lens (CL) Wearer • Poor CL hygiene • Immune-competent

THE CANDIDATE

• ACANTHAMOEBA • HARTMANELLA • NAEGLERIA • VAHLKAMPFIA

ETHIOLOGY

• ACANTHAMOEBA (genotypes T1-18) • T2, T3, T4, T5, T6, T10, T11 y T15 • T4 Causes 100%-85% of ocular acanthamoebiasis • In our case series in the last 5 years:

T4 T3 T11 ETHIOLOGY

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ETHIOLOGY

TROPHOZOITE CYST

LIFE CYCLE

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• Incidence 1-8% Microbial keratitis • CONTACT LENS WEARER (85%) • Soft contact lens • Orthokeratology • Multiuse solutions • Bath or use of contaminated waters/well water • NON CONTACT LENS WEARER (3-15%) • Trauma associated with contaminated waters • Surgical trauma • Use of well water and unnoticed corneal trauma

EPIDEMIOLOGY- RISK FACTORS

• Traumatic event related with water or contaminated soils • Contact lens wearer with poor hygienic care • Poor response to conventional antibacterial treatment • Disproportionate Pain

CLINICAL SIGNS OF AWARENESS

CLINICAL MANIFESTATIONS

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EPITHELIOPATHY

EARLY CLINICAL MANIFESTATIONS

EPITHELIOPATHY

EARLY CLINICAL MANIFESTATIONS

PERINEURAL INFILTRATES (Almost Pathognomonic)

EARLY CLINICAL MANIFESTATIONS

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LIMBITIS

EARLY CLINICAL MANIFESTATIONS

CORNEAL ULCERATION

LATE CLINICAL MANIFESTATIONS

RING INFILTRATE

LATE CLINICAL MANIFESTATIONS

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CORNEAL ABSCESS AND PERFORATION

LATE CLINICAL MANIFESTATIONS

IRIS ATROPHY

EXTRACORNEAL MANIFESTATIONS- INFLAMATORY

CATARACT

EXTRACORNEAL MANIFESTATIONS- INFLAMATORY

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SCLERITIS

EXTRACORNEAL MANIFESTATIONS- INFLAMATORY

POSTERIOR SEGMENT ISCHEMIC INFLAMMATORY SYNDROME

EXTRACORNEAL MANIFESTATIONS- INFLAMATORY

INTRAOCULAR INFECTION

EXTRACORNEAL MANIFESTATIONS- INFECTIOUS

10 Arnalich - Ocular acanthamoebiasis

SCLERITIS

EXTRACORNEAL MANIFESTATIONS- INFECTIOUS

CLINICAL AWARENESS: CL, PAIN, NOT RESPONSIVE

DIAGNOSIS

SLIT LAMP EXAMINATION

DIAGNOSIS

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IN VIVO CONFOCAL MICROSCOPY

DIAGNOSIS

• IN VIVO CONFOCAL MICROSCOPY

DIAGNOSIS

• IN VIVO CONFOCAL MICROSCOPY

DIAGNOSIS

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• IN VIVO CONFOCAL MICROSCOPY • Sensitivity 50% • Specificity 65.8-81.6% • DO NOT RELY ON CONFOCAL FOR DIAGNOSIS IF THE RESPONSE TO THERAPY IS POOR

DIAGNOSIS

CORNEAL SCRAPE ( Include epithelium or stroma with a 27-30G needle) FOR: Smears Cultures in non nutrient Agar PCR DIAGNOSIS

CORNEAL BIOPSY DIAGNOSIS

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• Must be CYSTICIDAL • Effective if definitive treatment is started within 3-4 weeks from onset

TREATMENT

Minimum cysticidal concentration in ug/ml PHMB CHX 600 Propamidine

500 Neomycin Paromomycin 400 Polymyxin 300 Ketoconazole Fluconazole 200 Pentamidine 100 Sepazonium 0 Miconazole For 100% kill Clotrimazole

No role for topical amino-glycosides or azoles (except voriconazole) TREATMENT

POTENTIAL NEW THERAPIES

• Voriconazol (oral, intraocular, and topical) • UV Cross-linking treatment • Statins

TREATMENT

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DRUG ADMINISTRATION

• Hourly day and night for 2 days • Hourly day only for 3 days • Then reduce to 6x daily taper to 4x

Drug toxicity common!

TREATMENT

CONTROLLING CORNEAL INFLAMMATION

• Role of topical steroids- for deteriorating inflammation & pain • Defer for 2 weeks after started treatment • Only use with biguanides • Continue biguanides for 4 weeks after steroids are discontinued

TREATMENT

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TREATMENT OF PERSISTENTLY CULTURE POSITIVE KERATITIS

• Switch diamidines and biguanides • Increase concentration of eye drops • PHMB 0.06% or Clorhexidine 0.2% • Add oral Voriconazole • Cryotherapy (for infective scleritis) • Corneal graft • Recurrence common • Large diameter keratoplasty

TREATMENT

• DELAY ON DIAGNOSIS (>3 WEEKS) • STAGE 3 AT PRESENTATION • OLDER AGE • NON T4 KERATITIS

PROGNOSIS

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• University Institute of Tropical Diseases and Public Health fo the Canary Islands, University of la Laguna • Basilio Valladares • Jacob Lorenzo Morales • José Piñeiro • Carmen Martin-Navarro • Tropical Disease Unit of Hospital Universitario Ramón y Cajal Madrid, Spain • Rogelio López Vélez

ACKNOWLEDGMENT

17 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

CARMEN MICHAELA CRETU

University of Medicine and Pharmacy “Carol Davila” Colentina Clinical Hospital – Parasitology Department Bucharest

OCULAR LARVA MIGRANS CYSTICERCOSIS DIROFILARIASIS

CLINICAL CASE . 38 years old, male patient, worker . Medical history: Type II Diabetes, no insulin required . February 2011: R E Total uveitis, possible ocular toxocariasis Secondary glaucoma  RE progressive decrease of vision, up to perception of fingers’ movements, headache ‐ Biomicroscopic ex: Perikeratic congestion, epithelial corneal edema, iris hemorrhages and neovascular membrane → scars of the iris ‐ leuchocoria ‐ Fundus ex: difficult examination, hazy, inflammation of posterior vitreous, prominent papilla and papillary edema, retinal hemorrhages, narrow arteries and dilated veins ‐ Ocular pressure: 60 mmHg  LE normal ‐ Orbit X‐ray: normal, no eyeball foreign bodies ‐ US: RE hyper echoic vitreal areas, temporal retinal folds ‐ retinal detachment ‐ IRM head and orbit :REposterior, external and lateral inflammation, retinal folds and retinal detachment; maxillary sinusitis; ocular tumor is excluded ‐ Laboratory: hiperleucocytosis (11000/cmm), no Eo; liver and kidney normal function; blood glucose 144 mg/dl Inflammatory syndrome present (ESR 25/45 mm/h; FH 640 mg/ml) Toxocara IgG serology (ELISA) – positive Toxoplasma, CMV, Leptospira, Brucella serology ‐ negative

18 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

28.03.2011

Treatment: corticosteroids, diuretics, anti‐diabetics Referred to Infectious Diseases Department –Increased dosage of corticosteroids and Albendazole 800mg/day, for 10 days –worsened

Referred to Ophthalmology and Parasitology Dept in Bucharest March 2011: RE Ocular pressure 44mm HG Fundus ex: vitreal inflammation, retinal folds, macular edema, retinal granuloma Toxocara avidity –AI 0.46 (recent infection, less than 20 weeks) Treatment: progressively decreased corticosteroids plus Diethylcarbamazine

May 2011: RE Fundus ex: ‐ Vitreal inflammation, retinal folds, macular edema, retinal granuloma ‐ Central Retinal Vein Thrombosis Toxocara serology ‐ positive

November 2011: RE disorganized Fundus ex: Total optic nerve atrophy Central Retinal Vein Thrombosis SEQUELS Vitreous precipitates

RE RE RERE

28.03.2011 28.03.2011 28.03.2011 RE RE

18.05.2011 18.05.2011

19 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

IMAGING DIAGNOSIS

Ocular MRI –retinal detachment

Ocular US –vitreal reaction, retinal folds

LARVA MIGRANS SYNDROME

LM Syndrome –migration of some nematode larvae, through the tissues of parathenic host, after invading the host either by digestive (ingestion of infective eggs) or subcutaneous penetration of the larvae.

(Schantz and Michelson, 1992) LMV est une migration prolongée et la longue persistance des larves du parasite, habituellement un nématode, dans les organes internes d’une hôte anormale (paratenique). (Petithory et al., 1994)

VLM - Toxocara canis - Spirometra spp. - Toxocara catii Etiology - Toxocara vitulorum - Balysascaris spp. - Parascaris equorum - Gnathostoma spp. - Ascaris suum

LIFE CYCLE

Toxocara canis adults (Cretu & Mihailescu )

Toxocara spp. eggs (Cretu & Mihailescu)  Eggs need soil development  The disease is due to the larval stage in human tissues  During the migratory stage, larvae are trapped in tissue granulomas  The life cycle remains unaccomplished, larvae wondering and remaining in the tissues  The pathology is due to the antigenic stimulation produced by the migrating larvae and tissue granuloma reaction ! Congenitally transmission of Toxocara larvae in dogs (puppies ‐ important source of infection)

20 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

TRANSMISSION

 Accidental ingestion of fertilized egg (vegetables, dirty hands etc…)

L T Glickman and J‐F Magnaval, 1993. Zoonotic roundworm infections. Inf Dis Clin North America. 7(3): 717‐731

 Consumption of raw chicken liver, cattle meat or rabbit giblets

K Nakagura et al: 1989 Toxocariasis possible caused by ingesting raw chicken. J Infect Dis 160: 735‐ 736

D Sturchler et al: 1990 Transmission of toxocariasis. J Infect Dis 571: 572

Espana et al: 1993. Secondary urticaria due to toxocariasis: possibly caused by ingesting raw cattle meat. J Invest Allergol Clin Immunol. 3(1): 51‐52

Y Morimatsu et al. 2006. A familial case of Visceral Larva Migrans after ingestion of raw chicken liver: appearance of specific antibodies in BAL of the patients. Am J Trop Med Hyg. 75(2):303‐396

RISK FACTORS FOR VLM AND OLM

Host associated risks Environmental risks Visceral Larva Migrans

• Children • Lower socio‐economic status • Black race > white • Rural residence Contact with puppies at home, or with • Pica/geophagia • soil contaminated with T. canis eggs • Consumption of raw liver

Ocular Larva Migrans

• Children • Contact with puppies at home or with • Pica/geophagia soil contaminated with T. canis eggs

(Glickman, 1993)

PATIENTS WITH TOXOCARIASIS CONSIDERING THE RISK FACTORS (200 CASES)

(Cretu et al., 2002)

21 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

“URBANIZATION” ?

TOXOCARA SEROLOGY IN BLOOD DONORS (85 persons)

About 2% oh the healthy people tested in UK had positive serology(Cretu et al., 2002) (Rook & Straughton, Dermatologica, 1972) …Seroprevalence 8,2% in psychiatric patients

(Huminer et al, 1992)

SOIL SAMPLES EXAMINED FOR PARASITES EGGS (200 samples)

(Cretu et al., 2002)

22 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

CLINICAL ASPECTS IN TOXOCARIASIS (200 cases)

According to: ‐ Parasitic burden ‐ Larval distribution ‐ Repetition of infection ‐ Host background ‐ Host immune response

(Cretu, 1998)

OLM – PATHOGENIC ASPECTS • Hypothesis of alife larvae (GRANULOMA)  mechanical and immunological action (ES‐Ag)  duration of immobilization  larval degree of encapsulation ‐ Intraocular larvae and lesions are mobile: continue the migration outside the lesion ‐ Larvae: ‐ become encapsulated inside a granuloma → dead, necrotic center ‐ ‐ escape outside the granuloma ‐ ‐ remain viable for long time • Hypothesis of dead larvae (ENDOPHTALMITIS) Local hypersensitivity reactions are consequent to semi‐necrotic, somatic or antigenic material, belonging to the dead larvae INCREASED RESISTANCE OF THE HOST  GRANULOMA HIGH HYPERSENSITIVITY  ENDOPHTALMITIS

Acquired immunity: due to a long contact to the larvae early outburst to the presence of the larvae

23 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

CLINICAL PRESENTATION

60 years old, male patient Onset May 2012: LE progressive decreasing of vision, headache, red eye, foreign body sensation, skin rash, pruritus, urticaria, migrating poliarthralgya  Medical history: High blood pressure, diabetis melitus type 2, no insulin required  Ophthalmology: LE Fundus ex: hazy vitreous, difficult examination (few data); RE normal  Laboratory: Inflammatory syndrome ‐ present (ESR, Fg, CRP) Normal WBC with Eo =20,41% (1881x103/ц)ᶮ Liver and kidney function –normal; serum glucose – 144mg/dl ElISA Toxocara –negative ELISA Toxo IgM ‐ negative and IgG positive  Diagnosis: Ocular toxoplasmosis  Treatment: alternative 3 weeks courses of Azithromicyne, Rovamycine, Clindamycine, associated to local and systemic corticosteroids No ocular improvement; Secondary glaucoma December 2012 OF: DNA Toxo positive Sera: Toxo IgG pos; IgE neg Bucharest WB Toxocara – positive Total IgE positive Persistent hyper Eo

DG: CONCOMITANT OLM & TOXOPLASMOSIS VA: LE perception of hand movements and light RE cataract OP: LE 28mm Hg; RE 18 mm Hg Fundus ex: LE – difficult to visualize retina Alternative treatment: DEC Pyrimethamine + Azitromyhcine + NAIS (local, general)

RT PCR Toxoplasma –ocular fluid

D.A.(8781) –Western Blot Toxocara canis D.A.(8868) –Western Blot Toxocara canis (sera) (ocular fluid)

24 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

Follow up:

- 2 courses DEC + corticosteroids ‐ decreased (permanent control of OP), than NSAI ‐ Pyrimethamine + Azithromycine + NSAI (local and general) ‐ Clindamycine + NSAI (local and general)

March 2013 –RE Cataract surgery VA 1 ‐ LE perception of light (secondary glaucoma and cataract)

August 2013 ‐ RE ‐ VA normal ‐ LE perception of light (secondary glaucoma and cataract) surgery

October 2013 –RE ‐ VA normal ‐ LE –surgery VA 1/20

OLM – RETINAL GRANULOMA

Male, 26 yo, Gorj county; No relevant medical history; animal contact ‐ September 2012: LE progressive blurred vision, scotoma Local hospital – corticosteroids→ transient improvement ‐ January 2013 Bucharest, Universitary Teaching Hosp, Ophthalmology VA: RE normal; LE 1/3 OP: normal Anterior segment: LE conjunctival hyperemia Fundus ex: Papilla undefined borders dilated veins white yellowish activeactive fofoci,ci, between macula and papilla, aboutabout 1 PD diffuse and extended sub‐retinal hemorrhages Dg: Suspicion ‐ LE OLM Laboratory: Serology for Toxoplasma IgM & IgG negative Serology for Toxocariasis – borderline, with low IgG Avidity Index WB positive Treatment: Albendazole + corticosteroids (increased liver enzymes –ABZ intolerance) DEC 2 courses Follow up: significant imprimprovementovement –r–ree‐sorbtion of hemorrhages, no moremore acactivetive lesions

RE LE

(Voinea & Cretu, 2013)

P.L . ( 1229) –Western Blot Toxocara – positive

25 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

CONCOMITANT OLM & VLM

3 years old girl .Atopic dermatitis  acute urticaria . Epigastric pain . LE ‐ Red eye ‐ Photophobia ‐Decreased and blurred vision . Fundus ex: ‐ Retinal granuloma ‐ Leucochoria . WBC 12.400/cmm ‐ Eo 17% Corticosteroids: local systemic . Liver function normal . Chest X Ray normal . Abdominal US non‐homogenous HSM . Stool ex for parasites –negative . ELISA Toxocara negative . WB positive for Toxocara . Toxoplasma IgM & IgG –negative 35 KDa 24 KDa

CONCOMITANT OLM & VLM

Vitreal reaction ‐ Retinal folds

VLM –US: non homogenous liver, with hyperechoic areas corresponding US ‐ retinal detachment due to posterior to Eo granulomas (old lesions) granuloma and vitreal reaction associated (Cretu and Ristea, 2000)

CONCOMITANT OLM AND TOXOPLASMOSIS

• M.M., 52 y.o., Ploiesti, Prahova county

• CASE HISTORY: ‐ VIII 1997 –Both eyes progressive decrease of vision (RE>LE) –Dg. Both eyes macula chorioretinitis – Treat. with local and general steroids  transitory improvement

‐ X 1997 –Dg. RE papilla tuberculoma  corticosteroids plus TB medication

for 1 year  no significant improvement

‐ III 1998 –reconsidered Dg and suspected RE ‐ OLM Retinal granuloma –

serological confirmation

• POSITIVE DG: ‐ Both eyes reactivated toxoplasmic chorioretinitis ‐ RE Toxocara subretinal granuloma

• TREATMENT: alternative DEC and Pyrimethamine/Sulphadoxine + corticosteroids

• EVOLUTION: ‐ OLM – clinical cured (scar) and serological improvement ‐ Toxoplasmosis –hyper‐pigmentated, inactive scar

26 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

POSTERIOR GRANULOMA BEFORE AND AFTER DEC THERAPY

L E R EL E R E III 1998 IX 1998 ‐ Ophthalmology: VA RE 1/30; VA LE 1/20 ‐ Ophthalmology: VA RE 1/30; VA LE 1/10 Visual field –RE central scotoma ‐ Fundus RE –important decrease of retinal granuloma, local exudates totally Fundus RE: ½ PD atrophic pigmented scar, disappeared, persistence of a reduced local 2xPD White‐yellowish temporal swelling, retinal swelling, hyper pigmentation of the retinal folds and small sub retinal chorioretinitis lesions, without any haemorrhages inflammatory activity ‐ELISA Toxocara ‐ Positive ‐ ELISA Toxocara – Positive ‐ ELISA Toxoplasma IgM negative, IgG positive ‐ IgG ELISA Toxoplasma positive (Ristea &Cretu, 1998)

OCULAR LARVA MIGRANS

Erhard & Molk Shields Ristea &Creţu Kernbaum (1979) (1983) (1984) (2000) Cr. endophtalmitis Cr. endophthalmitis Posterioar Posterior Peripheral + retinochoroiditis granuloma granuloma Retinal detachment Peripheral Mobile larvae Posterior Posterior granuloma retinochoroiditis Acute granuloma Peripheral granuloma Papillitis endophthalmitis Other forms Endophthalmitis Chronic ‐ hemorrages Pars‐planitis Mobile larvae in endophthalmitis ‐ larvae Optic Neuritis retinal layer Anterior chronic embolization Keratitis Unilateral uveitis ‐ papilitis Uveitis‐iritis diffuse ‐ hyalitis Hypopion sub acute ‐ iridocyclitis Mobile Larvae in neuroretinitis ‐ cataract vitreous cavity Keratitis ‐ cheratitis Conjunctivitis ‐ orbital lesions Lens opacities

OLM - LOCALIZATION

75 CASES

Mobile larvae Acute endophthalmitis

Anterior uveitis

Retina granuloma (Voinea & Cretu, 2009) Chronic Posterior endophthalmitis granuloma

27 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

OCULAR TOXOCARIASIS RETINAL GRANULOMA

Fundus examination Active lesion Chronic lesion

(Ristea and Creţu, 2000) (Voinea & Cretu, 2002)

(Voinea & Cretu, 2013)

(Cretu & Vintila, 2007)

OCULAR TOXOCARIASIS

Fundus examination Mobile larvae Fundus examination Vitreal reaction (Ristea &Creţu, 2000) (Ristea & Creţu, 2000)

Total uveitis Neuroretinitis (Ristea & Creţu, 2000) (Voinea & Creţu, 2009)

OLM DIAGNOSIS

 Epidemiology and Risk factors  Clinical symptoms/signs General Complete ophthalmological examination  Laboratory: ELISA E/S antigens Avidity tests and WB (OF, sera) W B ‐ Western Blot (OF, sera) WBC and Eo level, RBC Total and specific IgE Inflamatory biological syndrome (CRP, ESR, Fg) Liver and muscle enzymes, Gamma GT ECP  Pathology: eosinophylic granuloma  Imagery: X Ray, US, CT, OCT, AFG

28 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

OLM – ULTRASONOGRAPHY ANGIO FLUOROGRAPHY

RE – OLM RE – OLM RE – OLM Horizontal scan Longitudinal scan‐ Transversal scan meridian 9

RE – OLM LE – OLM Retinal detachment Endophthalmitis

OLM IMAGING DIAGNOSIS IRM OCT Diffuse, hyper dense, well defined area, located at posterior pole without any changes following contrast medium, no calcifications

LE Retinal granuloma

RE‐Retinal detachment (Voinea & Cretu, 1999; 2013)

DIFFERENTIAL DIAGNOSIS OF OLM

Retinoblastoma: dg. earlier than 2 years of age, vitreous and anterior pole clear - retinal detachment, no vitreal folds, no cataract associated - Imagery – calcifications of tumor (never in OLM) - OF: LDH OF/plasma > 1 (OLM < 1) OF phosphoglucose- isomerase/plasma > 2/1 (OLM decreased), no EO presence of tumor cells - negative serology or OF

Coats’ disease: unilateral, boys 6-12 y o, retinal tele-angiectasia + exudates → RD

Persistent primary vitreous hyperplasia: congenital, unilateral, microphtalmia, cataract associated sometimes

Prematurity retinopathy – history of prematurity, bilateral, temporal, peripheral

Family exudative retinopathy – bilateral, affecting other family members, bilateral macular retinal folds

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DIFFERENTIAL DIAGNOSIS OF OLM

Peripheral idiopathic uveoretinitis – often bilateral, chronic recurrent inflammation of retinal peripheral vessels and cilliary processes, multiple white exudates of pars plana, uveitis, retinal granuloma

Toxoplasmosis – often bilateral, active lesion associated to old foci, flat retinal lesion (elevated in OLM)

Hystoplasmosis – affects optic disc, in adults, atrophic peripapillar chorioretinitis, peripheral retinal scars

 Idiopathic neovascular subretinal membrane – in adults, unilateral, lack of other signs on FE, negative serology for Toxocara

Optic neuritis – malnourishment, toxins, post infection, vasculitis, tumors, MS etc…

Other ocular helminthes (Cysticercs, Trichinella, Loa loa, Onchocerca, Sparganum)

TB – flictenular conjunctivitis, uveitis, retinal granuloma

TOXOCARIASIS – INFECTION OR DISEASE ? INFECTION DISEASE

 Asymptomatic pts  Various and different intensity clinical signs considered as  Hazardously discovered VLM, OLM or CT hypereosinophilia  Can induce differential  Specification of diagnosis diagnosis, as they cam mimic  Epidemiological studies to neurological, heart, ocular, detect toxocariasis prevalence CNS, dermatological, !! TREATMENT –NOT NECESSARY respiratory disturbances etc… !! NECESSARY TREATMENT

Taylor et al, 1987, 1988 Beaver et al, 1952 Magnaval, 1994 Glickman and Shantz, 1981, 1987 Bass et al, 1987 Taylor et al, 1987

TREATMENT

 Specific medication • Diethylcarbamazine • Albendazole • Ivermectine • Flubendazole • Thiabendazole  Anti‐allergic medication  Steroid and non‐steroid anti‐inflammatory medication

30 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

H7C3 S N O ALBENDAZOLE NH COO CH3 DIETHYLACRBAMAZINE C H 2 5 N N N H3C C N H H (ABZ) (DEC) C2 5 Action: Action: • Selective depletion of cytoplasmic • Piperazine derivate, very efficient on mf tubules at the digestive epithelium level and Toxocara larvae and parasite cuticle • Muscle activity and block the parasite by • Decrease glucose intake  glicogen hyper‐polarisation effect depletion • Changes on the parasite’s surface Side effects: membrane, which become vulnerable to the host defense mechanisms • Abdominal pains, headache, nausea, • Inhibition of PG production vomiting, alopecia •Increase Eo and neutrophils cyto‐toxicity • Leucopenia, anaemia Side effects: • Increased liver enzymes • Transitory increased WBC and Eo • To be avoided in pregnant woman and • Transitory anorexia, headache, nausea children under 12 months Posology: 3‐4mg/kg/day for 7‐21 days Posology: 10‐15mg/kg/day; 21‐30 days, OLM, CNS → 6mg/kg/day for 21‐30 according to the clinical status and location days Fatty meals, liver protection

OCULAR LARVA MIGRANS CYSTICERCOSIS DIROFILARIASIS

• 44 years old female patient • Complaints: Left eye red, increased tears, photophobia • Ophthalmology : Dg. Episcleritis Anterior segment evaluation: light examination + slit‐lamp bio‐microscopy Posterior segment: indirect ophthalmoscopy episcleritis nodules chemosis palpebral edema • Laboratory: high WBC with normal Eo; inflammatory syndrome; liver enzymes raised • Treatment: NSAI local and general –no improvement Corticosteroids local and general –transient improvement • 5 months later: Dg. Choroid malignant melanoma ‐ suspicion progressive deterioration of VA –up to light perception headache –hemicranias painful eyeball and peri‐ocular tissue severe photophobia

31 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

• Ophthalmology: ‐ LE intense perikeratic hyperemia, dark purple ‐ Posterior corneal precipitates ‐ Anterior chamber unequal, narrowed temporal superior ‐ Pupil midriasis, decreased reflex ‐ Normal ocular pressure ‐ Fundus ex: immobile, grey tumor‐like formation, which determines temporal and macular retinal detachment, covering papilla, visible with 10 OD

• US: Suspicion of ophthalmic parasitic disease inflammatory retinal detachment, with multiseptum cystic aspect

• Positive diagnosis: Ocular cysticercosis

• Laboratory: ESR 120mm/1h; Fibrinogen 1149mg/dl Increased WBC – 16000/ccm, with normal Eo Toxocara serology –negative Toxoplasma serology –negative T. solium Abs – positive (ELISA) Coprology– negative for Taenia spp. eggs

PZQ CORTICOSTEROIDS

(Cretu &Corbu, 2000)

• Treatment Corticosteroids –local and general (Prednison 1mg/kylo/day, for 7 days, than progressively decreased) Praziquantel 50mg/kylo/day, divided into 3 equal dosages, for 2 weeks • Follow up 2 weeks: ‐ disappearance of ocular pain and perikeratic hyperemia ‐ LE VA 1/8 ‐ inflammatory syndrome and hyperleucocitosis – normal ranges ‐ Fundus ex. ‐ reduced retinal detachment, except temporal area ‐ US ‐ applied retina, except temporal inferior area 1 month: ‐ LE VA 1/3 ‐ normal range of hematological and biochemical parameters ‐ weakly positive serology ‐ Fundus ex. – applied retina, small scar ‐ US –no retinal detachment 3 months: ‐ stable

32 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

Cysticercus cellulosae: multi-organ involvement

 Invaginated scolex in a vesicle full of liquid  Transmission: - Swallowing T. solium infective eggs containing oncospherae - Auto/hetero-infection  Located: subcutaneous / adipose tissue muscles eyes CNS  Easily visible by the naked eye  Resistance: 40 days +4 0C; 40 hours -100C; destroyed +560C

- Spherical / ovoid shape vesicle - 5-15mm diameter - muscles forms - 8-12X5-6mm diameter parenchymal forms - inward - collagen fibres, micro-villosities - 3 muscle layers - Scolex - 4 suckers, rostellum and hooklets - liquide content - immunogenic, allergenic Cysticercus celulosae

- branched, no scolex - anarchic development under-arachnidan space or inside of cerebral ventricles - 10 - 20 cm

33 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

Ocular cysticercosis: (http://t2.gstatic.com)  Viable, non encapsulated larvae penetrate the eye by blood vessels: central retinal artery, posterior cilliary artery, leading to retinal detachment  Most common locations: - vitreous, retina (75-80% of the cases) - orbit, eyelid, conjunctiva (20-25% of the cases) - chorioretinitis, conjunctivitis, uveitis, iridocyclitis  Usually unique  Brain damage can disturb eye function at all segments level (decrease visual field and acuity, fundus exam shows abnormalities, oculomotor nerves - III, IV, VI pairs)  Important orbital reaction - unilateral exophthalmia  Palpebral location – rare, can mimic chalasion  Conjunctiva: 5-15mm, local inflammation, reddish or yellowish, painless

Rare (about 2-7% of all cysticercosis cases) Very dangerous and painful Evolution  inflammatory syndrome: lid and corneal oedema, conjunctivitis, uveitis  tumour like signs: exophthalmia intra-ocular foreign body sensation blurring or loose of vision scotoma constant headache distortion of images sensation of light flashes

 Vitreal location rapidly photophobia Slit lamp examination - peristaltic, dynamic movements of the larvae Scolex - evaginated or invaginated inside of the vesicle  Subretinal reactions rapidly significant decrease / loose of vision larval presence - retinal detachment, or cystoid macular edema  Peripheral locations frequently without symptoms

 Fundus examination: intraocular cyst, 1-3 papilla diameter in size, grey or yellowish, transparent, with refringent scolex  Disintegrated / dead cysticercs induce a serious inflammatory reaction around rapid and progressive loose of vision

 Mobile larvae - seen in aqueous humor or vitreous locations Fixed larvae - between choroid and retinal membranes

34 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

 Neurocysticercosis (NCC) influences the visual acuity and the entire eyeball: - location of the cysts along the optic nerves - brain and meningial reactions eliciting optic and oculomotor nerves damage - increased intra-cranial pressure and consequently on the anterior part of the optic analyzer

 Oculomotor nerves damage is the most important effect of NCC: - paralyzing of the extrinsic muscles of the eyeball - palpebral ptosis - diplopia - changes of pupilar reflexes - midriasis

CLINICAL SIGNS & SYMPTOMS

 Painless vision loss secondary to a parasitic infection by presumed subretinal cysticercosis  Mild to severe vision loss

Lombardo J. TLC Northwest Eye, Seattle, Washington 98133, USA. Subretinal cysticercosis. Optometry & Vision Science. 78(4):188-94, 2001 Apr.

 Restriction of vision movements Chung GW. Lai WW. Thulborn KR. Menner C. Blair NP. Pulido JS. Magnetic resonance imaging in the diagnosis of subretinal cysticercosis. American Journal of Ophthalmology. 134(6):931-2, 2002 Dec.

Padey PK. Chaudhuri Z. Bhatia A. Extraocular muscle cysticercosis presenting as Brown syndrome. American Journal of Ophthalmology. 131(4):526-7, 2001 Apr.

Pandey PK. Chaudhuri Z. Sharma P. Bhomaj S. Extraocular muscle cysticercosis: a clinical masquerade. Journal of Pediatric Ophthalmology & Strabismus. 37(5):273-8, 2000 Sep-Oct.  Moving viable motile larvae: conjunctivitis – anterior/posterior uveitis

Corbu C. Pop M. Cretu C. Coiculescu M. Tatu M. Ocular cysticercosis - case report. Oftalmologia. 51(1):37-9, 2001

CLINICAL SIGNS & SYMPTOMS Serial US and CT were done for 20 patients, receiving medical treatment. The most common clinical presentation: - proptosis (9/20) with restriction of ocular movements - subconjunctival cyst - subretinal cyst - papillary-edema - atypical optic neuritis - lid nodule - intra-retinal cyst - associated brain parenchyma involvement is quite rare Pushker N. Bajaj MS. Chandra M. Neena..Ocular and orbital cysticercosis.. Acta Ophthalmologica Scandinavica. 79(4):408-13, 2001 Aug. Acquired Brown syndrome (after trauma, iatrogenic events, cysts of superior oblique muscle tendon and inflammation) - pain and swelling in the superior nasal orbit - ocular motility limitation (limitation of elevation in adduction) - recurrent attacks of conjunctivitis and diplopia in up gaze Rao VB. Sahare P. Varada V. Acquired brown syndrome secondary to superior oblique muscle cysticercosis. Journal of Aapos: American Association for Pediatric Ophthalmology & Strabismus. 7(1):23-7, 2003 Feb

Pandey PK. Chaudhuri Z. Bhatia A. Extraocular muscle cysticercosis presenting as Brown syndrome. American Journal of Ophthalmology. 131(4):526-7, 2001 Apr.

35 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

CLINICAL SIGNS & SYMPTOMS

A 13- to 14-mm live cysticercus larva was found, removed from the eye and confirmed by histopathologic examination

Nainiwal S. Chand M. Verma L. Garg SP. Tewari HK. Kashyap S. Ophthalmic Surgery, Lasers & Imaging. 34(6):464-6, 2003 Nov-Dec.

Sub retinal cyst evident on fundus examination was investigated by US - cystic structure - MRI of the orbit confirmed the suspicion for cysticercosis - Cerebral cyst was associated (left occipital lobe of the brain)

Chung GW. Lai WW. Thulborn KR. Menner C. Blair NP. Pulido JS. Magnetic resonance imaging in the diagnosis of subretinal cysticercosis. American Journal of Ophthalmology. 134(6):931-2, 2002 Dec.

The most common location of the larvae is sub retinal or vitreal

Wittig EO. Ocular cysticercosis: an epidemiological study. Arquivos de Neuro-Psiquiatria. 59(3-B):696-701, 2001 Sep. Wabbels B. Kruse F. Helmke B. Rohrschneider K. Volcker HE. Painless orbital swelling after sojourn in tropics. Cysticercosis and other parasitic eye diseases]. Klinische Monatsblatter fur Augenheilkunde. 217(2):109-13, 2000 Aug.

CLINICAL SIGNS & SYMPTOMS

A 30-year-old man complained about a painless orbital swelling in the absence of general symptoms. - The patient's history - travel to India as well as South East Asia - Orbital examination - normal eyeball - MRI scan and B-scan US - orbital cyst with a diameter of 1 cm - Histopathological examination of a whitish intra-orbital mass removed: cream-white, thin walled cyst with a single central invaginated scolex with suckers and hooklets

Wabbels B. Kruse F. Helmke B. Rohrschneider K. Volcker HE. Painless orbital swelling after sojourn in tropics. Cysticercosis and other parasitic eye diseases. Klinische Monatsblatter fur Augenheilkunde. 217(2):109-13, 2000 Aug.

The symptomatology began with uveitis worsened in 10 days by greater inflammation in spite of successive corticosteroids, antibiotic and antiviral therapy. - Repeated examination and serological and radiological investigations did not help establish the etiology - Vitrectomy - the vitreous containing cysticercus.

Guigon B. Trepsat C. Intraocular cysticercosis: a difficult diagnosis]. Journal Francais d Opthalmologie. 25(1):78-80, 2002 Jan.

CLINICAL SIGNS & SYMPTOMS

Optic nerve damage is another rare but possible localization of cysticercs.

Bousquet C F, Dufour T F L, Derome P C E. Retrobulbar optic nerve cysticercosis. Case report. Journal of Neurosurgery. 84:293-296, 1996 Feb. Menon V, Tandon R, Khanna S, et al. Cysticercosis of the optic nerve. Journal of Neuro- Ophthalmology. 20(1):59-60, 2000

High index of suspicion should be entertained for extra-ocular muscle in every case of recent acquired ocular motility disorder

Pandey PK. Chaudhuri Z. Sharma P. Bhomaj S. Extraocular muscle cysticercosis: a clinical masquerade. Journal of Pediatric Ophthalmology & Strabismus. 37(5):273-8, 2000 Sep-Oct.

36 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

Cysticercosis was confirmed:

‐ US or CT scan revealed a cystic lesion, with or without scolex ‐Cyst without scolex with positive response to medical treatment ‐ cysticercosis confirmed histo‐pathologycally after surgery  duration of onset 7,9 +/‐ 10,53 months

DIAGNOSIS – MULTIDISCIPLINARY TEAM

DIAGNOSIS – MULTIDISCIPLINARY TEAM Ophthalmological evaluation: presence of larvae (number, size, location, viability)

Living form: undulating expending and extracting ”pearl”, with intermittent evagination and invagination of the protoscolex

Klots S, Penn C.C., Negvesky J.G., Burtus S.I. Fungal and parasitic infections of the eye. Clincal Microbiological Reviews.13(4): 662-685, 2000 October

Parasite morphology:

- look for T. solium eggs in stool ‐ Histopathology after surgical removal ‐ presence of larvae and peri‐cystic reaction depending on its viability

Immunology: sera, spinal fluid, aqueous humour ‐ ELISA, EITB, WB

‐ Molecular Sera – at least 2 bands ‐ Eo in ocular fluid CSF – at least one specific band

37 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

DIAGNOSIS – IMAGING  Ocular US, CT, IRM Useful in intra-ocular and intra-orbital parasitosis Follow up of the patients' pathology Determining the best therapeutic approach

(Cretu &Corbu, 2000) (Voinea & Cretu, 2010)

(Rosca &Cretu, 2000) (Voinea & Cretu, 2005)

29 patients with ocular parasites: - Vitreous membranes –47% (10) ‐ Posterior vitreous detachment – 28% (6) ‐ Vitreous opacities – 100% (29) ‐ Partial detachment – 50% (3) ‐ Minimum findings – 19% (4) ‐ Total detachment –50% (3) ‐ moderate findings – 71% (15) ‐ Intravitreous cysticercs – 5% (1) ‐ severe findings –9% (2) ‐ Vitreoretinal tractions –33% (7) ‐ Cyclitic membrane –5% (1) ‐ Retinal detachment – 28% (8) ‐ Granuloma – 66% (14)

IMAGERY

 Look for other possible locations:

- Soft tissues X ray - muscle calcifications - CT / IRM - diagnosis and case monitoring for cerebral locations - Ventriculography - Mielography

RE Orbital cysticercosis‐ opic nerve (Voinea & Cretu, 2011)

38 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

TREATMENT  Surgical removal of the larvae

A total of 25 patients with ocular cysticercosis were retrospectively analyzed Majority of larvae could be surgically removed without residual effects However, four patients (16%) had no useful vision left in the involved eye. David S. Mathai E. Ocular cysticercosis--a review of 25 cases..Journal of the Association of Physicians of India. 48(7):704-7, 2000 Jul. For subretinal cysticercosis seems to be the best choice

Lombardo J. TLC Northwest Eye, Seattle, Washington 98133, USA. Subretinal cysticercosis. Optometry & Vision Science. 78(4):188-94, 2001 Apr. Sabrosa NA. Zajdenweber M. Nematode infections of the eye: toxocariasis, onchocerciasis, diffuse unilateral subacute neuroretinitis, and cysticercosis. Ophthalmology Clinics of North America. 15(3):351-6, 2002 Sep. Luger M H A et al. In-toto removal of the subretinal Cysticercus cellulosae by pars plana vitrectomy. British Journal of Ophthalmology. 78:561-63, 1991

For retrobulbar optic nerve - can be applied Busquet Ch F, et all. Retrobulbar optic nerve cysticercosis. Journal of Neurosurgery 84: 293-96, 1996

! Clinical, serological and imaging monitoring is recommended

PRINCIPLES

Individualized ‐ Number, location ‐ Viability

Larval growth ‐ life threatening →active management ‐Antiparasitic ‐Surgery

Management of intracranial/intraocular hypertension

Antiepileptic

39 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

TREATMENT !! use of alternative courses is recommended  Medical treatment !! only for viable or partially disintegrated cysticercs Praziquantel: 25-50mgs/kilo/day, every 8 hours, for 15-30 days Corbu C. Pop M. Cretu C. Coiculescu M. Tatu M. Ocular cysticercosis - case report. Oftalmologia. 51(1):37-9, 2001 Albendazole: 15-20 mgs/day, twice a day, with the fatty meals, for 21-30 days

Pandey PK. Chaudhuri Z. Bhatia A. Extraocular muscle cysticercosis presenting as Brown syndrome. American Journal of Ophthalmology. 131(4):526-7, 2001 Apr.  Symptomatic Sedation, antiepileptic analgesic and steroids - for ocular and CNS locations

Corticosteroids ‐ Dexamethasone 4,5‐12mg/day ‐ Prednisone 1mg/kilo/day ‐ to reduce the symptoms due to the death of the parasite ‐ to reduce the frequency of shunt blockage and consequently the shunt failure (for NCC) ‐ decrease PZQ serum concentrations, but does not affect its parasiticidal activity Anticonvulsivants ‐ useless in vitreal localizations –lack of blood vessels, limited penetration ‐ Phenytoine and carbamazepine serum levels decreased in association with praziquantel

COENURUS CEREBRALIS

Larval stage of Taenia multiceps multiceps

DH intestine of dogs, foxes and other canides, accidental in humans

- Cerebral localizations are more common

- Ocular locations are rare - Anterior segment – severe uveitis - Retrolental - Orbital cystic tumor like mass - Subretinal lesions - Subconjunctival Otranto D.,Ebertart M.L., Zoonotic helminths affecting the human eye. Parasites and vectors. Clinical signs: 4(41): 2011 red and painful eye complications: glaucoma, retinal fibrosis, blindness

Treatment: only surgical removal of the cyst

40 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

TAENIA CRASSICEPS

• Adult stage in carnivores’ intestine → eggs

• Immune-compromised and rare in immune-competent (EU, USA)

• Larvae take the blood stream and reach subretinal and anterior chamber

• Clinical signs: asymptomatic iridocyclitis retinitis

Otranto D., Ebertart M.L., Zoonotic helminths • Treatment: surgical intervention affecting the human eye. Parasites and vectors. 4(41): 2011

SPIROMETRA SPP SPARGANOSIS • Adult stage in carnivores’ intestine → eggs • Infection in humans: - drinking polluted water - plerocercoid larvae - eating infected IH (frogs, birds, snakes – plerocercoid larvae reach subretinal and anterior chamber) • Reported cases in Central Europe, South America, Asia • Localization: → muscles, subcutaneous tissue, uro-genital, abdominal viscera, CNS → eye: conjunctiva and subconjunctiva • Clinical signs: itching (local granulomata) local pain, epifora, chemosis, ptosis conjunctivitis, foreign body sensation, hyperemia • Treatment: surgical intervention

Otranto D., Ebertart M.L., Zoonotic helminths affecting the human eye. Parasites and vectors. 4(41): 2011

OCULAR LARVA MIGRANS CYSTICERCOSIS DIROFILARIASIS

41 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

CLINICAL CASE

32 YO female, never leaving Romania No relevant medical history ‐ Complaints: 07 October 2012 ‐ LE redness, transient eyeball pain, foreign body sensation, increased ocular tears, mild blurred vision, eyelid redness and edema ‐ Clinical exam: no fever, lymph nods, liver, spleen or lung disturbances ‐Laboratory: Hypereosinofilia (12%), Normal liver and kidney function Thin & thick blood film ‐ negative ‐ Ocular exam: conjunctival hyperemia, appearance of a round worm wondering under the conjunctiva Stanescu & Cretu, 2012 Ocular nematoda ‐ Dirofilaria spp.

Multiplex PCR for simultaneous detection and discrimination of Dirofilaria immitis and Dirofilaria repens Gioia G, Lecová L, Genchi M, Ferri E, Genchi C, Mortarino M. 2010. Highly sensitive multiplex PCR for simultaneous detection and discrimination of Dirofilaria immitis and Dirofilaria repens in canine peripheral blood. Vet Parasitol. 172(1-2):160-3. Line 5: Sample 1. Amplification products of approximately 500 bp for the genus Dirofilaria and of 204 bp for D. immitis. Line 6: Sample 2. Amplification products of approximately 500 bp for the genus Dirofilaria and of 204 bp for D. immitis. Line 7: Sample 3. Amplification products of Line 1: D. immitis positive control. Amplification products of approximately approximately 500 bp for 500 bp for the genus Dirofilaria and of 204 bp for D. immitis. Line 2: D. the genus Dirofilaria and repens positive control. Amplification products of approximately 500 bp for the genus Dirofilaria and of 327 bp for D. repens. Line 3: D. immitis/D. of 204 bp for D. immitis. repens co-infection. Amplification products of approximately 500 bp for the genus Dirofilaria, of 327 bp for D. repens and of 204 bp for D. immitis. (by courtesy of Prof. Fernando Line 4: Negative control Simon, Salamanca)

First human case was described in 1880, by the famous Romanian pathologist and microbiologist Victor Babes Babes V. Über einen in menschihen Peritonaum gefunden nematoden. Arcs Anat. Physiol. Klin. Med. 81,158‐165 (1880)

‐ 1885 ‐ Babesia spp and babesiosis (Haemosporidiae) ‐ 1888 ‐ he created in Romania the 2nd Center, after France, for vaccination against rabies ‐ “Babes‐Negri bodies” ‐ cellular inclusions in rabies infected nerve cells ‐ “Babes‐Ernst bodies” ‐ metachromatic inclusions in cytoplasm of gram‐positive bacteria (diphtheria) 04.07.1854 – 19.10.1926 ‐ demonstrated that Pellagra is a disease of misery ‐ …he contributed to studies on rabies, TB, leprosy, diphtheria and other infectious diseases

42 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

BACKGROUND: • Human dirofilariasis, produced by the tissue location of nematode worm Dirofilaria spp, is spread in tropical, subtropical and recently in worm temperate regions, including United States, Europe, Japan, Australia

• At least 15 species of mosquitoes are responsible for the transmission of the disease, as well as culicoids and black flies ‐ Simulium for D. ursi

• Based on the presence or absence of external longitudinal cuticular ridges, there are two subgenera currently described: Dirofilaria dirofilaria and Dirofilaria Nochtiella

• Dirofilaria species infecting humans are: D. immitis and Dirofilaria Nochtiella: D. tenuis, D. repens (Europe, dogs), D. ursi, D. subdermata, D. striata, D. tenuis (USA, raccoons).

• The most common locations of immature filarial worms in humans are the connective tissue (D. repens), lungs, eye (D. immitis). Recently 2 cases with adults removed were documented, in Amazon region (Otranto & Eberhard, 2011; Otrando et al, 2011))

• The largest number of filarioid eye infections is caused by Dirofilaria spp., migrating across the conjunctiva, or encapsulated in a nodule on the conjunctiva or eyelid

• Ocular damage is usually due to D. immitis, but extremly rare, D. repens can wonder to this site (Otranto et al 2011)

DH (dog) MF  Adult = 180 days HUMANS (paratenic host) – Parasite remains immature  NO MF Immature parasite migrate in the lungs, connective tissue or the eye

WOLBARCHIA ENDOSYMBIONT

 Many filarial species including D. immitis, harbor gram negative intracellular bacteria Wolbarchia endosymbiont (Casiraghi et al., 2001, Parasitology. 122:93‐103)

 Wolbarchia is found in hypodermis of all the developmental stages of male and female parasite, including the reproductive organs of the female worm (Kramer et al., 2003, Parasitol Res. 89:381‐86)

 Wolbarchia is involved in the inflammatory reaction and in the polarization of the host immune response against the parasite (Bazzocchi et al., 2004, Vet parasitol, 117:73‐83) (Marchon at al., 2004, Vet Parasitol, 125:313‐321) (Simon et al.,2003, Clin Diagn Lab Immunol, 10(1):180‐181)

43 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

CLINICAL ASPECTS: • Asymptomatic ‐ many cases (56%) (Otranto et al., Emerg Infect Dis: 2011, 17(5);863‐866)

• Lung lesions ‐ NODULES (coin lesions), peripheral, sharply defined, incidentally discovered ‐ Extremely rare, can migrate to pulmonary artery, followed by pulmonary infarct ‐ 76% right lung ‐ 10% ‐ moderate hypereosinophilia (Flieder D et al., Hum Pathol: 1999, 30:251‐256)

• Ocular locations ‐ Migration of the worm under conjunctiva: pruritus, pain, edema, congestion of conjunctiva (Dordevic et al., 2010, UDC: 616.995.132007) ‐ Intraocular structures penetration (rare): photophobia, diplopia, foreign body sensation, floaters etc) (Otranto et al., Emerg Infect Dis: 2011, 17(5); 863‐866) ‐ Onchocerca lupi: under conjunctiva

RETROSPECTIVE ANALYZE OF 22 CASES:

• Non of the patients traveled or lived outside Romania • Age: 6 ‐70 YO ‐ Male = 12; Female = 10 ‐ Medium range: 36,2 y.o. • Residence in Romania: U = 10; R = 12 ‐ Bucharest, Ilfov, Teleorman, Cluj‐Napoca, Tulcea, Valcea, Galati, Brasov, Ialomita, Giurgiu counties

44 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

RESULTS:

• Locations of 22 cases

• Eye: 12 cases ‐ under conjunctiva = 6 cases ‐ palpebral = 4 cases ‐ orbit = 2 cases

• Lungs: 3 cases

• Soft tissues: 6 cases ‐ Thigh = 3 cases ‐ Axils = 1 case ‐ Forehead = 1 case ‐ Abdominal = 1 case

• Nostrils: 1 case

DIAGNOSIS: • Clinical • Imaging • Histopathological • Molecular • Serology – useless • Mild/moderate eosinophilia

TREATMENT:

• Complete removal of the nematoda (Otranto & Eberhard, 2011) Granuloma ‐ calcifications • If incomplete Granuloma – abscess with subsequent purulent expulsion of the parasite • No antiparasitic treatment is necessary (Nimir et al., 2012) • DEC – successful in some cases (Klotz et al., 2000)

OCULAR DIROFILARIASIS

Palpebral Conjunctiva

45 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

OCULAR DIROFILARIASIS surgical removal of the larvae

SKIN NODULE Dirofilaria repens

 62 YO, female patient, rural residence

 History: February 2011 surgical intervention for inguinal hernia

 2 months latter, nearby surgical scar, skin nodule, painless,

2 cm diameter ‐ excision

 Pathologist: granulomatous tissue, parasitic formation in the central area

 Serology for Toxocariasis and Cysticercosis negative

 Analyzing the slides and the tissue blok ….

Dirofilaria repens

Morphological characteristics: ‐ Cross sectional diameter ‐ approximately 200mf ‐ Presence of longitudinal ridges ‐ On the tick‐layered cuticle the ridges are separated by a distance larger than the width of the ridge itself. (D. immitis ‐ smooth cuticle)

46 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

PALPEBRAL NODULE Dirofilaria repens (06.2010)

Male Male Male Terminal extremity cuticle details Anterior part

FOREHEAD NODULE

D. repens

47 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

Although the incidence of the discovered dirofilariasis is sporadic and therefore the public health importance does not seem to be high, the continuous increasing number of diagnosed cases during the last 2 years, and considering the increasing number of scientific papers on this topic, impose direct attention to this zoonosis, since the incidence may rise with the improvement of clinical diagnosis  Possible emergent disease Not only in Romania, but also in Balkan and European regions

OTHER FILARIOID OCULAR PARASITES:

‐ Wuchereria bancrofty & Brugia malayi ‐ Oncocerca lupi ? under diagnosed

Figure 1 A‐C (case 1). A, Conjunctiva excision of the fibrous mass tissue with the extracted nematode tightly beneath the sub‐conjunctiva. B and C: Longitudinal view of the cuticle of the nematode before fixation (B) and after haematoxylin and eosin staining showing the external prominent ridges (black arrows) and two internal striae (yellow arrowheads) per interridge (bar = 30 μm). D‐F (case 2; Masson‐Goldner trichrome staining). D, Worm sections in the inflammatory infiltrate (bar = 600 μm). E, Oblique and sublongitudinal section showing the cuticle with ridges (black arrows) and two striae (reddish) (yellow arrowheads) per interridge, and muscles cells (bar = 50 μm). F, Transverse section in anterior part with narrow lateral chord, developed muscle cells, thin intestine and two uteri (bar = 50 μm).

vierme.avi

48 Cretu - Ocular larva migrans, cysticercosis, dirofilariasis

MANY THANKS

• PATRICIA MIHAILESCU ‐ Eco‐Para‐Diagnostic Medical Centre, Bucharest

- University of Medicine and Pharmacy “Carol Davila” • LILIANA MARY VOINEA ‐ Emergency Universitary Teaching Hospital –Ophthalmology Department, Bucharest • CATALINA CORBU MONICA POP ‐ University of Medicine and Pharmacy “Carol Davila” • ‐ Ophthalmological Emergency Hospital, Bucharest • SERGIU MALIS

• DIANA STANESCU ‐ West Eye Hospital, Bucharest

Email: [email protected]

49 Yera - Ocular toxoplasmosis

Management of ocular toxoplasmosis

H. Yera, E. Delair, A. P. Brézin, J. Dupouy-Camet Departments of Parasitology Mycology & Ophthalmology, Hôpital Cochin, AP-HP, Université Paris Descartes, Paris, France

Ocular toxoplasmosis (OT)

Major cause of posterior uveitis worldwide

Complication of both acquired acute or reactivated congenital toxoplasmosis

Clinical signs depend on inflammatory reaction and localization of lesions

Prognosis depends on localization of retinal lesions

Am J Ophthalmol. 2008;146(6):851-5

425 cases, France: 23% acquired 15% congenital

but…62% of unknown origin

50 Yera - Ocular toxoplasmosis

Clinical manifestations

 Peripheral retinal lesions: no or minor visual acuity effects

 Macular retinal lesions: major vision effects

 Optic nerve involvement: visual field defects, color vision loss

 Anterior uveitis

 Vitritis

Delair et al. 2011 Ocular Immunol Imflam.

Diagnosis

Ophthalmology, Hôpital Cochin Ophthalmology, Hôpital Cochin

Ophthalmologic arguments:  toxoplasmosis specific lesions (fundus examination)  rapid response to treatment

Typical lesions of OT

o Macular o Active lesion, satellite of pigmented scar

Ophthalmology, Hôpital Cochin

oPeripheral o Active lesion, satellite of pigmented scar

Ophthalmology, Hôpital Cochin  Confirmed by positive toxoplasmic serology

51 Yera - Ocular toxoplasmosis

Typical lesions of OT

o Macular oScar

Ophthalmology, Hôpital Cochin

oPeripheral o Active lesion, satellite of pigmented scars

Ophthalmology, Hôpital Cochin  Confirmed by positive toxoplasmic serology

Typical lesions of OT

o Papillary o Active lesion

Ophthalmology, Hôpital Cochin

 Confirmed by positive toxoplasmic serology

Atypical lesions of OT

o Extensive lesions o Inflammatory reaction o Hemorrhages

Ophthalmology, Hôpital Cochin

 Paracentesis or vitrectomy for aqueous humor or vitreous humor analysis

52 Yera - Ocular toxoplasmosis

Atypical lesions of OT

Ophthalmology, Hôpital Cochin

 Ocular fluids analysis  Low volume (5-100 µL)

 Biological diagnosis of OT

 Differential microbiologic diagnosis: herpes virus, rubella, syphilis, toxocarosis

Biological diagnosis of OT

 Positive serology:  Confirmed typical lesions of OT  Does not proved OT

 Ocular fluids analysis:  Detection of local anti-T. gondii IgG synthesis - Goldmann-Witmer coefficient - Comparative Western-blot

 Detection of T. gondii DNA by PCR

Goldmann Witmer coefficient

Quantitative detection of local specific IgG synthesis:

Dosage of specific IgG by IIF or ELISA Levels of total IgG by immunodiffusion technique

GWC = (Anti-T. gondii IgG / total IgG) ocular fluid (Anti-T. gondii IgG / total IgG) serum

GWC ≥ 2 : in favor of OT

Requires minimum 50 µL ocular fluid

Sensitivity 45% Specificity 93%

Talabani et al. 2009 J Clin Microbiol.

53 Yera - Ocular toxoplasmosis

Comparative Western-blot

Qualitative detection of local specific IgG synthesis: additional bands more intense bands Toxoplasma Western blot IgG/IgM kit (LDBIO diagnostics, France)

 Requires only 10 µL ocular fluid

Sensitivity 53% Specificity 100%

Serum Ocular fluid Talabani et al. 2009 J Clin Microbiol.

Real time PCR

 TaqMan® assay targeting T. gondii 529 bp region repeated 200 to 300 times

 Nucleic acid was extracted from 5 to 50 µL of ocular fluid with QIAamp DNA Micro kit (Qiagen)

 Sensitivity 58% Specificity 100%

Talabani et al. 2009 J Clin Microbiol.

Combination of 3 biological tests

• Making best use of the low volume of ocular fluid

• 2 by 2 combinations of tests increased the sensitivity to  80% GWC and PCR  73% Western-blot and PCR  70% Western-blot and GWC

• Combining 3 tests leads to 85% sensitivity and 93% specificity

Talabani et al. 2009 J Clin Microbiol.

54 Yera - Ocular toxoplasmosis

Relation clinics & tests results

 Higher delay between onset of symptoms and aqueous humor collection:  In patients with positive GWC and Western-blot

 Larger size of acute necrotising retinitis:  In patients with positive PCR

 Higher occurrences of chorioretinal scars or degree of intraocular inflammation:  In patients with positive GWC

Talabani et al. 2009 J Clin Microbiol.

Algorithm of biological tests according the clinical data

Treatments

 If visual acuity effects

 Pyrimethamine + sulfadiazine + folinic acid

or pyrimethamine + azithromycin + folinic acid

3 weeks

 Corticoid

Bosch-Driessen et al. 2002 Am J Ophthalmol.

55 Yera - Ocular toxoplasmosis

Case reports

Case 1

Case 2

Case 3