hydrocele [وضع التوافق]

HYDROCELEIN

LYMPHATIC FILARIASIS

INTRODUCTION:

Ò Of the three parasites causing lymphatic filariasis(LF), Wuchereria bancrofti accounts for over 90%of the global burden; about 120 million cases whichinclude 83.63 million cases of microfilaria carriers,16.02 million cases of lymphoedema and 26.7916.02 million cases of lymphoedema and 26.79million cases of hydrocele. This clearly shows thatthe burden of genital manifestations of filariasis interms of hydrocele is higher compared tolymphoedema (Pani et al., 2005).

LF SPECTRUM

Ò Lymphatic filariasis (LF), caused by W. bancrofti,presents a spectrum of clinical states with twomajor poles:

Ò One pole is represented by microfilaremic patientswith high parasite numbers and down-regulatedcell mediated responses.cell mediated responses.

Ò The other by patients with lymphedema andhydrocele, which typically have few or noparasites but vigorous specific immune reactions.

Ò The prevalence of overt clinical manifestationsamong adult residents of endemic areas is usuallyless than 10% for lymphedema and 30-50% forhydrocele (Debrah et al., 2007).

UROGENITAL DISEASEÒ Dreyer and colleagues, 2002 emphasized the

distinction between lymphoedema of the scrotaland penile skin, which has the same pathogenesisas lymphoedema of the limbs, and swelling due toincreased fluid inside the cavity of the tunicavaginalis.vaginalis.

Ò This fluid, which is usually considered to be'hydrocele', actually is comprised of several distinctentities including true hydrocele, chylocele andhematochylocele. The term 'filaricele' has beensuggested recently to include all of thesemanifestations (Ottesen and Weil, 2004).

HYDROCELE IN EGYPT:

Ò Bancroftian filariasis is focally endemic in Egypt and prevalence rates are increasing in some areas (Harb et al., 1993). These infections are often clinically silent; however, hydroceles are the most common clinical manifestation of filariasis in Egypt common clinical manifestation of filariasis in Egypt (Faris et al., 1998).

AGE DISTRIBUTION OF HYDROCELE

Ò In endemic areas, the prevalence of hydrocele shows an age dependent rise. A distinct monotonic increase in age prevalence is seen. In most Asian and African stable endemic sites, the prevalence of hydrocele can be as high as 50% in older age classes above 45 years of age (Michael et al., classes above 45 years of age (Michael et al., 2004).

SOCIO-ECONOMIC BURDENÒ The social impacts of the disease in terms of physical

disfigurement, loss of self-esteem, lowered employmentopportunity, interference in sexual activity and familydiscord poor marriage prospects, stigma within thecommunity, poor job opportunities are common.The degree of stigma is associated with the severityÒ The degree of stigma is associated with the severityand visibility of the disease.

Ò There is a considerable psychosocial stress on theindividual and families including anxiety/depression,sexual disabilities of men afflicted with hydrocele andfinally the poor quality of life of individuals with thedisease is obvious (Pani et al., 2005).

RISK FACTORSÒ Age and infection intensity are important risk

factors for hydroceles. There is a steadyprogression of lymphatic dilation with age andinfection intensity (Dreyer et al., 2002). Also humanhave shown that vascular endothelial growthfactors (VEGF)-A gene promoter polymorphism isfactors (VEGF)-A gene promoter polymorphism isan important risk factor for the development ofhydrocele in patients infected with W. bancrofti(Veikkola et al., 2001).

EPIDEMIOLOGICAL USES OF HYDROCELEDETECTION:

Ò It is important to understand that hydrocele beingthe predominant manifestation in Bancroftianfilariasis, detection of scrotal swellings among afixed number of males in study sites by trainedhealth workers has been found to be a validhealth workers has been found to be a validmethod of rapid assessment procedure .

Ò Therefore, data obtained for scrotal swellingprevalence by physical examination of males byhealth workers can also be used for rapidepidemiological mapping for filarial diseaseprevalence and disease burden estimation.

CLINICAL GRADING OF HYDROCELE

Ò (Melrose, 2004):Ò 0 NormalÒ 1 Swelling of spermatic cordÒ 2 Swelling up to 10 cm in diameterÒ 2 Swelling up to 10 cm in diameterÒ 3 > 10 cm in diameter

PATHOGENESIS:

Ò It was suggested that true filarial hydrocele istriggered by death of the adult worm, whichproduces an inflammatory nodule that occludes thelymphatic vessel. In this study, the incidence ofacute hydrocele following a single 'scrotal noduleevent', whether spontaneous or induced by DEC,was 22% (Noroes et al., 2003). Of these, 24%was 22% (Noroes et al., 2003). Of these, 24%persist to become chronic.

Ò Lymph vessel dilation, not obliteration, is probablythe early event following antigenic stimulation,which takes place while the adult worms are stillalive, i.e. when offspring larvae are being released.

PATHOGENESIS:

Ò Many of the released larvae are degenerate and will be taken up by phagocytic cells; it is known that exposure of phagocytes to filarial antigens is accompanied by triggering of the innate immune system, with the release of not only pro-inflammatory cytokines but also of molecules that inflammatory cytokines but also of molecules that promote lymphangiogenesis (Hise et al., 2007).

PATHOGENESIS:

Ò Role of Wolbachia:Ò In addition to antigens released from the worm

itself, those from its Wolbachia endosymbionts appear to play a major role in pathogenesis, as their depletion by doxycycline leads to a reduction of elevated plasma levels of lymphangiogenesis of elevated plasma levels of lymphangiogenesis factors, which precedes the reduction of lymph vessel dilation (Debrah et al., 2006).

MOLECULAR MECHANISMS OF PATHOGENESIS:

Ò It was found that vascular endothelial growth factors (VEGF) control angiogenesis and lymphangiogenesis in humans (Cao et al., 1998; Veikkola et al., 2001). The VEGF family comprises five members, Ò The VEGF family comprises five members, including VEGF-A, a potent regulator of normal and abnormal angiogenesis.

Ò Over-expression of VEGF-A in the skin of mice results in increased vascular density, enhanced leucocyte adhesion, and tissue infiltration and also promotes lymphangiogenesis .


Ò Over-expression of VEGF-C in the skin oftransgenic mice results in lymphatic endothelialproliferation and dilation of lymph vessels.

Ò Signals for endothelial cells are mediated throughVEGF Receptor-2 in blood vascular endothelialcells, and generally via VEGF Receptor-3 in thecells, and generally via VEGF Receptor-3 in thelymphatic endothelial cells.

Ò The expression of VEGF-A and VEGF-C has beenshown to be up-regulated by pro-inflammatorycytokines, such as IL-1β, TNF and IL-17 (Numasakiet al., 2004), suggesting that pro-inflammatorycytokines affect the lymphatic vessels via VEGF-Aand VEGF-C (Asano-Kato et al., 2005).


Ò Major inducers of pro-inflammatory mediators are theWolbachia essential endosymbionts of filariae.Wolbachia have been shown to stimulate pro-inflammatory cytokines, such as TNF, IL-1β and IL-6,and nitric oxide. This stimulation is known to mediatethe upregulation of VEGFs (Cho et al., 2007).the upregulation of VEGFs (Cho et al., 2007).

Ò This pro-inflammatory cytokines such as TNF and IL-1βinduced by Wolbachia could affect lymphatic vessels byinduction of VEGFs.

Ò Those findings are consistent with elevated serumlevels of VEGF-A and endothelin-1 as well as VEGF-Cand VEGFR-3 found in filaria-infected patient (Esterreet al., 2005; Debrah et al., 2006).


Ò In hydrocele patients, targeting the Wolbachiaendosymbionts by doxycycline led to a reduction inplasma levels of VEGF-A, with consequentialamelioration of the size of hydrocele.

Ò These data are in agreement with the hypothesisthat progression of infection to hydrocele may bethat progression of infection to hydrocele may becontributed to by the over-expression of vascularand lymphangiogenic factors such as VEGF-A.


Ò Secretion of VEGF-A molecules in the scrotal region ofhydrocele patients could be responsible for:

Ò (i) extravasation and accumulation of fluids, plasma,lymph, etc. from the blood and lymphatic vessels intothe scrotal region, resulting in the formation ofhydrocele, chylocele and lymphocele.hydrocele, chylocele and lymphocele.

Ò (ii) formation of nodules in hydrocele patients which areusually observed just before hydrocele developmentwhen DEC is administered.

Ò The formation of these nodules might result from thedeath of adult worms due to DEC treatment, whichwould in turn lead to liberation of VEGF-A, in part dueto release of Wolbachia (Debrah et al., 2009).

PROGNOSTIC INDICATORS FOR HYDROCELEPATHOLOGY:

Ò Plasma levels of VEGF-A/VEGF-C/sVEGF-R3 may correlate with disease progression in LF leading to LE and hydrocele, and hence, might be used as prognostic indicators of an increased risk of LF prognostic indicators of an increased risk of LF pathology before it manifests.

PROGNOSTIC INDICATORS FOR HYDROCELE PATHOLOGY:

Ò This information could be explored in specialsituations in which either anti-VEGF-A or antiWolbachia treatment is administered to patientsdeveloping hydrocele to improve this condition inaddition to the classic anti-filarial treatment(ivermectin or DEC), which strongly reduces(ivermectin or DEC), which strongly reducestransmission but has no immediate improvement onthe pathology in patients, and may even exacerbatethe condition by the large release of Wolbachiaantigens due to Mf or adult worm killing.

GENETIC SUSCEPTIBILITY:

Ò Evidence has been presented that human VEGF-Agene promoter polymorphism is an important riskfactor for the development of hydrocele in patientsinfected with W. bancrofti.

DIAGNOSISÒ For several decades the only traditional way to

diagnose the filariasis infection caused by W. bancroftiwas by examining blood collected during the night aswell as in other fluids such as hydrocele fluid and urinefor the presence of microfilariae (MF) (Rocha 2000).

Ò Bancroftian filariasis is often under reported becausepeople with a low level of microfilaremia orpeople with a low level of microfilaremia oramicrofilaremia can be missed by the conventionalmicroscopic examination.

Ò The detection of circulating filarial antigens (CFA)(More & Copeman 1990) and non-invasive imagingtechniques (Amaral et al., 1994) created newalternative method in the diagnosis of bancroftianfilariasis.

ULTRASOUND AND FILARIAL DANCE SIGN:

Ò Several studies have shown that adult W. bancroftican be detected in the scrotal area of infected menby ultrasound (Amaral et al., 1994; Faris et al.,1998; Dreyer et al., 2002).

Ò It was reported that these adult worms are foundmostly in dilated intrascrotal lymphatic vessels, andmostly in dilated intrascrotal lymphatic vessels, andthat the locations of the worm nests are stable overtime.

Ò The typical movement of these filariae, called thefilarial dance sign (FDS), provides an opportunity toobserve the adult worms in vivo (Amaral et al.,1994).


Ò At the same time, ultrasound examination offers amethod to detect pathological changes, such as thedegree of dilatation in the lymphatic vessels, earlyand advanced stages of hydrocoele, and thenumber of worm nests over time.Examination by ultrasound is a non-invasive toolÒ Examination by ultrasound is a non-invasive toolthat will become increasingly important in the long-term observation of lymphatic filariasis Studies.

Ò Additionally, the movement of adult worms wasdocumented in higher resolution by Pulse WaveDoppler, seen as an undulating band (Faris et al.,1998; Mand et al., 2003).


Ò Pulse Wave Doppler (PWD) mode was proved tobe a useful technique and has advantage over b-and m-mode imaging and Colour Power Doppler(CPD).

Ò Adult worm were detected by b-mode imaging aswavy bands and the body wall of the adult wormwavy bands and the body wall of the adult wormappeared as double layers within the dilated lymphvessels.

Ò In CPD, the movement of the lymphatic fluid (by theadult worms) in the dilated lymphatic vessels couldbe visualized in form of a red colour signal.


Ò PWD technique facilitate the examination byallowing differentiation of scrotal lymphatic vesselswhich have bidirectional movement characteristic ofthe filarial dance sign from arteries and veins thathave characteristic appearance with unidirectionalflow (Faris et al., 1998; Mand et al., 2003).flow (Faris et al., 1998; Mand et al., 2003).

FOUR-STAGE GRADING SCHEME WAS DEVELOPED FOR HYDROCELEASSESSEMENT USING ULTRASONOGRAPHY

Ò To quantify improvement/worsening of hydrocele, a staging system using ultrasonography of the scrotal area has been developed (Debrah et al., 2007).

Ò Stage 1: Sub clinical hydrocele.Ò Stage 2: The maximal longitudinal and transverse

diameters of the hydrocele do not exceed 1.9 and 1.6 diameters of the hydrocele do not exceed 1.9 and 1.6 cm, respectively.

Ò Stage 3: The maximal longitudinal and transverse diameters of the hydrocele do not exceed 3.8 and 3.2 cm, respectively.

Ò Stage 4: The maximal longitudinal and transverse diameters of the hydrocele are greater than 3.8 and 3.2 cm, respectively.

CIRCULATING FILARIAL ANTIGEN (CFA):

Ò Detection of circulating filarial antigen has emerged asalternative pathway for the diagnosis of W. bancroftiinfection.

Ò Commercial kits utilizing specific monoclonal antibodiesto detect W. bancrofti antigens are currently available.

Ò ELISA based on Og4C3 monoclonal antibody hasÒ ELISA based on Og4C3 monoclonal antibody hasbeen used to diagnose microfilaremic as well asamicrofilaremic individuals with high specificity.

Ò Also, whole blood immunochromatographic (ICT)filariasis card test has been developed using the AD12.1 monoclonal antibody with high specificity andsensitivity to W. bancrofti antigen (Nuchprayoon et al.,2003).

USE OF HYDROCELE FLUID IN DIAGNOSIS OF LF:

Ò The availability of monoclonal antibodies Og4C3(More & Cooperman 1990) and AD.12 (Weil et al.1997) which can be used in ELISA andimmunochromatography, respectively, havebecome important for filariasis diagnosis inbiological fluids.biological fluids.

Ò In the past seven decades many researchers havebeen interested in utilizing the hydrocele fluid toobtain and isolate CFA from W. bancrofti.

TREATMENTÒ It was found that no effect of DEC treatment (as

mass treatment) on hydrocele volume. As well,treatment with DEC can provoke both acute andchronic hydrocele in men with W. bancroftiinfection.

Ò Surgery is the recommended intervention forÒ Surgery is the recommended intervention forhydrocele (hydrocelectomy), it is regarded ascurative.

Ò Other techniques, such as aspiration of the fluidand injection of sclerosing substances, are lesseffective, have unacceptable side effects, and havenot been adequately evaluated in filariasis-endemicareas.

TREATMENTÒ The risk of recurrence after eversion may be

substantial. Thus, current WHO guidelines call forcomplete removal of the tunica vaginalis.

Ò Because some hydrocoeles appear to reversespontaneously and surgical morbidity is high inmany filariasis-endemic areas, non-invasivephysiologic measures such as deep breathing haveproved useful in the management of non-filariallymphedema.

hydrocele [وضع التوافق]

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