A Diagnostic Algorithm for Patients with Intracranial Calcifications

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1 A Dignostic Algorithm for Ptients with Intrcrnil Clcifictions Algoritmo dignóstico en pcientes con clcificciones intrcrneles Kren Ntli Nieto Tord 1 Ctlin Wilches 2 Alejndr Mnrique 3 Key words (MeSH) Brin diseses Brin neoplsms Centrl nervous system diseses Multidetector computed tomogrphy Plrs clve (DeCS) Encefloptís Neoplsis encefálics Enfermeddes del sistem nervioso centrl Tomogrfí computrizd multidetector 1 Rdiology nd dignostic imging resident, Fundcion Universitri Snits, Bogotá, Colomi. 2 Neurordiologist, Deprtment of rdiology. Clinic Rein Sofi. residents, Teching ssistnt, Fundcion Universitri Snits, Bogotá, Colomi. 3 Rdiologist, Deprtment of rdiology. Clinic Rein Sofi. Teching ssistnt, Fundcion Universitri Snits, Bogotá, Colomi. Summry Intrcrnil clcifictions re n occsionl finding in computed tomogrphy nd cererl mgnetic resonnce imging. Their etiology is widely diverse nd comprises physiologicl nd pthologicl processes. This review pretends to descrie the intrcrnil clcifictions y n esy dignostic lgorithm, using the loction, morphology nd pttern in order to nrrow the differentil dignosis nd reduce the interprettion mistkes. Resumen Ls clcificciones intrcrneles son un hllzgo frecuente en los estudios de tomogrfí y resonnci mgnétic cererl. Su etiologí es mplimente vrid y comprende procesos tnto fisiológicos como ptológicos. Est revisión usc descriir ls clcificciones intrcrneles dentro de un lgoritmo dignóstico fácil de relizr por el rdiólogo, en el cul su loclizción, morfologí y ptrón pueden yudr reducir los dignósticos diferenciles y disminuir los errores por ml interpretción. Introduction Intrcrnil clcifictions re common rdiogrphic finding nd their pthogenesis vries from enign physiologicl processes to multiple pthologicl processes (1), their imging chrcteriztion ccording to their morphology nd loction is importnt to estlish differentil dignosis. Pthologicl clcifictions cn e clssified into five mjor groups: congenitl, tumor, infectious, vsculr nd metolic. The most frequent cuses of non-pthologicl or physiologicl clcifictions re those tht occur in: choroid plexus, sl gngli, dur mter, henul, prsitic crotid, petroclinoid ligment, pinel glnd, tentorium, sgittl sinus, cererl sickle nd lood vessels (2). Historiclly, conventionl rdiogrphy hs een used for the detection of clcifictions; however, with the dvent of technology, tomogrphy hs replced the use of conventionl rdiogrphy nd hs ecome the idel method for its evlution due to its high sensitivity in the visuliztion of one tissue nd clcifictions (3). Mgnetic resonnce imging (MRI) is lso useful in the detection of clcifictions with the use of T2 grdient echo sequences nd mgnetic susceptiility (4); however, its signl intensity in the T1 nd T2-weighted sequences mke it non-specific method for its visuliztion (5). Discussion Physiologicl clcifictions Intrcrnil physiologicl clcifictions hve no demonstrle pthologicl cuse nd re directly proportionl to ge; they cn e found from 5 yers of ge nd without ny preference for sex. These my pper in: Pinel glnd: Smll conicl structure locted in the midline etween the thlmic odies posterior to the henulr commissure; this glnd hs continuous growth during the first 2 yers of life, lter stilizes (6). Its clcifiction is not pthologicl unless it is ssocited with n increse in its size, which suggests neoplsm when the 4732

2 clcifiction is greter thn 1 cm (7). The incidence of clcifiction is 11% (8) nd histologicl reports of erly clcium deposits in fetl life hve een found in the literture (9); however, strting t ge 5 (Figure 1). Henul: Pir of ilterl nuclei locted in the dorsomedil inferior thlmus. It hs functions in pin processing, reproductive ehvior, nutrition, circdin cycle, response to stress nd lerning. When it is clcified, it hs curviliner pttern, nterior to the pinel glnd. An ssocition etween clcifiction nd dysfunction of the henul nd schizophreni nd lerning disorders in these ptients hs een reported in the literture (10). Its clcifiction is present in up to 10% in over 2 yers (11). Choroidl Plexus: Intrventriculr orgn responsile for the production of cererospinl fluid, locted in the lterl ventricles, with higher concentrtion in the ventriculr trium clled the choroidl glomus. The prevlence of choroidl plexus clcifictions vries etween 12 nd 16% (8, 12) (Figure 1). Dur-mtter: Meningel outer lyer composed of thick connective tissue tht covers the rin nd spinl cord, its clcifiction is more frequent in the tentorium, reported in the literture with frequency rnging from 2% to 20% (13). They come with lminr pttern. In nother loction, in the cererl sickle, clcifictions re visulized with pttern of dense flt pltes in the midline of the rin. It is importnt to rememer tht if these re oserved in young popultion, the seceous nevus syndrome should e ruled out (Figure 1c). Petroclinoid ligment nd sgittl sinus: Its clcifiction is relted to degenertion sites, dependent on ge, nd follow lminr nd discretely nodulr pttern. Bsl gngli: Its clcifiction is usully of idiopthic etiology with n incidence of % tht increses with ge with fine, dotted or thick, symmetricl nd conglomerte pttern (14); if it ppers in ptients younger thn 30 yers of ge, metolic pthology should e suspected (Figure 1). Pthologicl clcifictions Pthologicl clcifictions re divided into severl groups, s shown in Tle 1. Tle 1. Clssifiction of pthologicl clcifictions Congenitl Sturge-Weer syndrome Tuerous sclerosis Noncongenitl infections Chronic virl encephlitis Grnulomtous infection Metolic Vsculr Neoplstic Frh s disese Hypothyroidism Neurofiromtosis HIV infection Hypoprthyroidism Primry therosclerosis Cvernomtous mlformtion Arteriovenous mlformtion Oligodendrogliom Crniophryngiom Germ cell neoplsm Lipom Hyperprthyroidism Aneurysms Neurocytom Cockyne s syndrome Pseudohyperprthyroidism Chronic infrction Neuroectoderml primitive Tumor Gorlin Syndrome Posthyroidectomy Chronic vsculitis Ependymom TORCH (toxoplsmosis, ruell, cytomeglovirus, herpes simplex) Zik Gngliom Meningiom Medulolstom Pilocytic strocytom c Figure 1. Axil CT cuts of the simple skull: ) clcified pinel glnd, locted in the midline etween the lterl thlmic odies, posterior to the third ventricle, ) clcifiction of the sl gngli, choroid plexus nd c) clcifiction of the sickle interhemispheric in its posterior portion. Rev. Colom. Rdiol. 2017; 28(3):

3 Congenitl clcifictions Sturge-Weer syndrome: An uncommon neurocutneous syndrome, of spordic occurrence, with prevlence of 1 in 50,000 live irths (15). It is chrcterized y the ppernce of fcil nevus of port wine color, congenitl glucom nd leptomeningel ngiomtous mlformtion. The ltter genertes venous hypertension nd hypoperfusion of the cortex, cusing chronic ischemi, trophy nd corticl clcifictions with liner pttern, in doule or curviliner contour, predominting in convolutions, prietl nd occipitl (14) (Figure 2). Tuerous Sclerosis: Also known s Bourneville s disese is nother utosoml dominnt neurocutneous disorder (fcomtosis), with clinicl prevlence / penetrnce of pproximtely 1 in 6,000 to 12,000 live irths (16); is chrcterized y multiple enign tumor lesions derived from the ectoderm tht ffect the skin, nervous system nd eyes. Presents the clinicl trid of Vogt: mentl retrdtion, epilepsy nd seceous denom. Its most common mnifesttions include corticl-suependyml tuers, normlities in white mtter, crdic rhdomyoms nd renl ngiomyolipoms. There re multiple intrcrnil mnifesttions, the 4 most common re: corticl tuers, suependyml nodules, gint cell strocytoms nd normlities of the white mtter; suependyml nodules represent hmrtomtous chnges nd re ssocited with clcifictions in 88%, more common thn corticl tuers (17), nd the ventriculr trium is locted long the cudothlmic groove (Figure 3). Neurofiromtosis type 1: Known s Von Recklinghusen disese is the most common fcomtosis, with utosoml dominnt inheritnce, ut with spontneous onset in up to 50% of cses; ffects the skin, nervous system, ones nd endocrine glnds; its incidence is 1 per 2,000 live irths. Within their intrcrnil mnifesttions, glioms, dysplsis nd hmrtoms tht ffect the glous pllidus re present, ut rrely re clcified (18, 19) Lipoms: They re enign congenitl mlformtions, pproximtely 80-90% re locted in the midline; in its periphery nd towrds its cpsule cn e oserved curviliner or focl clcifictions tht limit with the surrounding prenchym (20). Cockyne Syndrome: An utosoml recessive disese mnifested y progressive encephlopthy ssocited with intrcrnil clcifictions nd white mtter lesions. Clcifictions re chrcterized y their sucorticl locliztion, in sl gngli nd dentte nuclei, re visulized with thick pttern (13). Gorlin-Goltz Syndrome: Also known s sloid cell nevus syndrome, it is rre utosoml dominnt fcomtosis, mnifested with multiple odontogenic kertocysts nd sl cell crcinoms. Its incidence is 1 per 60,000 live irths. For its dignosis it is necessry to fulfill two mjor criteri or one mjor nd two minor; ilmellr clcifiction is one of the lrgest. Infectious clcifictions Cn e clssified into congenitl nd cquired. Infection of the centrl nervous system (CNS) in the fetus cn e seen in lrge group clled TORCH, which includes toxoplsmosis, ruell, cytomeglovirus nd herpes virus infections. In herpes simplex there is extensive neuronl destruction, multicystic encephlomlci nd mnifests with scrring clcifictions s sequels, with thlmic, periventriculr nd in the convolutions. In the cse of congenitl toxoplsmosis, clcifictions occur predominntly in sl gngli, periventriculr nd cererl corticl, with dystrophic ppernce nd rndom loction; their size correltes with the time of infection (3) (Figure 4). Congenitl ruell is ssocited with meningitis, ventriculitis, ventriculomegly, nd periventriculr clcifictions in the white mtter, sl gngli nd rin stem. Cytomeglovirus infection is cused y DNA virus memer of the herpes virus fmily, is the most common congenitl infection nd ffects % of the orn. Trnsmission to the fetus requires close nd prolonged contct with respirtory secretions, urine, lood, trnsfusions. The most frequent findings due to centrl nervous system involvement re microcephly, hydrocephlus, corticl nd periventriculr clcifictions, punctiform or plque, periventriculr pseudocysts nd mlformtions of corticl development (Figure 5). Within this group of congenitl infections should e dded the infection y Zik virus, n rovirus of the fmily Flviviride tht in 2016 ws found in 28 countries. This virus identified in the cererl prenchym of the neworn destroys the developing rin, genertes microcephly nd crniofcil disproportion; the intrcrnil clcifictions re thick, loclized in the sl gngli nd in the corticosucorticl trnsition (21) (Figure 6). Among the cquired infectious diseses re virl encephlitis in its chronic phse, with encephlomlci nd residul clcifictions in the prenchym; tuerculous grnulomtous infections; nd opportunistic fungl infections. In the intrprenchyml tuerculoms the sign of the white hs een descried, y the representtion of centrl nest of clcifiction, surrounded y ring of enhncement, findings highly suggestive of tuerculosis compromise. Other cquired infectious pthologies where intrcrnil clcifictions re visulized re HIV, neurocysticercosis nd hydtid cysts. In neurocysticercosis it is possile to oserve densely clcified cyst tht my contin n eccentric dense nodule; findings tht represent ded lrv, similr to tht visulized in the hydtid cyst where the ded prsite is oserved s single septte or multiloculted clcifiction (Figures 7 nd 8). Metolic clcifictions Fhr s disese: Rre neurologicl disorder chrcterized y extensive symmetricl ilterlly clcifictions of sl gngli (stritum-ple). According to their loction they generte progressive dystoni, prkinsonism nd neuropsychitric mnifesttions. It egins to e symptomtic fter out 20 yers, nd one of its most common cuses is prthyroid disese (22) (Figure 9) A Dignostic Algorithm for Ptients with Intrcrnil Clcifictions. Nieto K., Wilches C., Mnrique A.

4 Figure 2. nd ) Axil CT cuts of the single skull: multiple frontl nd prietl corticl clcifictions with liner pttern, in ril or doule curviliner contour, comptile with the Sturge-Weer dignosis. Figure 5. nd ) Axil CT scn of the skull nd xil sequence with T1 informtion in ptient with cytomeglovirus congenitl infection: hydrocephlus, fine corticl clcifictions nd punctiform periventriculr plques forming. Figure 3. nd ) Axil CT scns of ptient with dignosis of tuerous sclerosis: suependyml nodules nd clcified prenchyml hmrtoms, s well s corticl tuers. Figure 6. nd ) Axil CT cuts of single skull in neworn with congenitl infection y Zik: Microcephly, crniofcil disproportion nd gross intrcrnil clcifictions re evident in the sl gngli nd in the re corticosucorticl. Figure 4. nd ) Axil CT scns of single skull: multiple clcifictions in sl gngli, periventriculr nd cererl corticl, dystrophic ppernce nd rndom locliztion in neworn with congenitl toxoplsmosis infection. Figure 7. () Axil CT scns of single skull in ptient with intrcererl tuerculom locted t corticosucorticl junction. ) Ptient with history of neurocystocercosis in the chronic or clcified phse: Severl punctiform clcifictions re visulized. Rev. Colom. Rdiol. 2017; 28(3):

5 Figure 8. ) Single skull CT scn in ptients with HIV dignosis: clcified lesion of left insulr locliztion, high gngliosl lesions on the sme side nd occipitl leptomeningel enhncement corresponding to the dignosis of cryptococcosis, infection cused y Cryptococcus neoformns. ). Ptient with unique dystrophic clcifiction, djcent to the nterior horn of the right lterl ventricle, with dignosis of toxoplsmosis in chronic phse, opportunistic infection more frequent in the ptient with HIV. Figure 9. Simple crnil CT in ptients dignosed with Fhr s disese: ilterl symmetricl clcifictions of the sl gngli. Prtohormone metolism disorders (hypo/ hyper/pseudohyperprthyroidism: The prtohormone hs the function of mintining serum clcium levels, then ny ltertion in the production of this hormone cn generte intrcrnil clcifictions. These re of preferentil loction in the dentte nuclei, sl gngli, thlmus nd peripherl sucorticl white mtter (22) nd my e ssocited with dyskinesis nd signs of extrpyrmidl (Figure 10). Vsculr clcifictions Clcifictions due to primry therosclerosis re proportionl to ge, common in the elderly, preferentilly locted in the internl crotid rtery, in its clinoid portion (60%), verterl rteries (20%), middle cererl rtery nd silr rtery (5%) (23) (Figure 11). Other vsculr cuses include rteriovenous, cvernomtous mlformtions nd neurysms. Arteriovenous mlformtions my pper s dystrophic clcifictions in the nest nd others with serpentine distriution long the vessels y 25-30%. Cvernomtous mlformtion or vsculr hmrtoms show typicl clcifictions in corn popcorn with n incidence of 40-60%; the neurysms my contin murl clcifictions nd more frequently if they re prtilly or totlly thromosed. Pthophysiologiclly, the mechnism of clcifiction of most of these lesions is secondry to chronic venous ischemi nd formtion of dystrophic clcifictions y hemorrhge (23) (Figures 12 nd 13). Neoplstic clcifictions In intrcrnil neoplsms with clcifictions, its evlution in conjunction with the ptient s ge, morphology nd tumor loction nrrows the dignostic possiilities. They cn e divided into two groups: extrxil nd intr-xil. Extrxil tumors, such s crniophryngioms occurring in dults, present with visul, endocrinologicl or intrcrnil hypertension, hve suprsellr locliztion nd show morphous nd loulted clcifictions (Figure 14); meningioms of durl origin re frequent in elderly people nd my hve vrile clcifictions in 3% (Figure 15). Intr-xil tumors re ssocited with hemorrhge y comintion of neovsculriztion, rteriovenous shunts, nd rpid tumor growth leding to necrosis nd disruption of intrcellulr clcium regultion, which ultimtely leds to clcium deposition. Within this group re the slow-growing oligodendroglioms, locted preferentilly in the frontl loe, show clcifictions in 40-90%, centrl, miroclcifictions or lumpy (23) (Figure 16). Medullolstoms re clcified y 10-20%. Other tumors do so in lesser percentges, such s those of the pinel glnd nd germ cells, in which it is rre for them to generte their own clcifictions. Pinel tumors re elieved to encompss existing clcifictions, with the exception of pinelstom tht my hve multiple nd peripherl clcifictions of its own. Other less frequent tumors tht re clcified include primitive neuroectoderml tumor, dysemriogenic tumor, gnglioglioms, pilocytic strocytom nd metsttic tumors of osteogenic srcom nd mucinous denocrcinom or secondry to rdiotherpy (24). Tumor clcifictions hve no pthologicl significnce, ut my suggest dequte response to tretment (25) (Figures 17 nd 18). Residul clcifictions posttretment or posttrum Another possile etiology of cquired clcifictions is scrring, either y surgicl tretment or y rdiotherpy or post trum, in which cse it is of vitl importnce to know the ntecedents nd idelly to hve the previous dignostic imges to ssess if clcifictions pper fter the trumtic event or tretment, whether or not this type of tumor is ssocited with clcifictions per se nd evluted in reltion to the other findings in the imge nd clinicl evolution (Figure 19) A Dignostic Algorithm for Ptients with Intrcrnil Clcifictions. Nieto K., Wilches C., Mnrique A.

6 c Figure 10. nd ) Axil CT cuts of the single skull in ptients with idiopthic hypoprthyroidism, pseudohypoprthyroidism nd hyperprthyroidism, who present in 70-80% clcifictions in the sl gngli, sucorticl, in dentte nuclei nd cereellum. Figure 11. nd ) Axil CT scn of the skull: clcifiction of the verterl rteries in their intrcrnil portion t height of the gret hole. Figure 12. Axil CT cuts of the single skull: ) Left frontl cererl rteriovenous mlformtion: clcifictions with serpentine distriution long the vessels. ) Aneurysm of the middle cererl rtery locted in the silvino vlley nd with fine posterointernl murl clcifictions. Figure 13. Axil CT scn of single skull. ) Gross loclized clcifiction in the right cererl peduncle in ptient with dignosis of cvernomtous mlformtion. ) MRI: xil sequence of mgnetic susceptiility: The typicl morphology in popcorn is visulized in cvernomtous mlformtion. Figure 14. ) Sgittl reconstruction in CT of the skull in ptient with crniophryngiom of suprsellr loction, with morphous nd loulted clcifictions. ) MRI xil sequence of mgnetic susceptiility where the clcifiction of suprsellr loction. Rev. Colom. Rdiol. 2017; 28(3):

7 Figure 15. Axil CT scn of skull in one window: right frontl clcifiction ssocited with focl thickening of the ones of the skull in ptient dignosed with meningiom. c Figure 16. nd ) Axil crnil CT scn of the skull: right frontl intrxil lesion with ssocited vsogenic edem nd centrl clcifictions lso oserved in MRI () s low-signl grouped imges, this finding is chrcteristic of oligodendroglioms. Figure 18. Axil cus toms of simple crnil tomogrphy in ptients dignosed with ) strocytom, ) suependimom nd c) PNET, where oth peripherl nd centrl clcifictions re visulized s well s thick intrtumorl locliztion. Figure 17. MRI Axil sequences of FLAIR nd mgnetic susceptiility where high signl lesion is visulized in the fourth ventricle with clcifictions in its interior in ptient dignosed with ependymom. Figure 19. Axil CT scn of the single skull: smll left occipitl intrxil clcifiction fter trum crnioencephlic A Dignostic Algorithm for Ptients with Intrcrnil Clcifictions. Nieto K., Wilches C., Mnrique A.

8 Dignostic Algorithm (Correlte with clinicl dt nd ssocited imging findings) Intr-xil Extrxil Unique Multiples Primry tumors nd metstses Vsculr mlformtions Distrophic Metstsis Primry tumors nd metstses Tuerculom Infections Fcomtosis Distrophic Distrophic Metolic Vsculr Figure 20. Dignostic Algorithm Conclusion For correct pproch of the intrcrnil clcifictions it is necessry to define, in the first instnce, if they re physiologicl or pthologicl; then, together with their loction, pttern nd morphology, clinicl informtion nd other findings in imges, to pproch possile differentil dignoses, in order to reduce the mount of them. References 1. Grech R, Grech S nd Mizzi A. Intrcrnil Clcifictions, Pictoril Review. The Neurordiology Journl 2: , Dghighi MH, Rezei V, Zrrintn S, Pourfthi H. Intrcrnil physiologicl clcifictions in dults on computed tomogrphy in Triz, Irn. Foli Morphol (Wrsz). 2007;66(2): Celzo FG. Brin stones revisited etween rock nd hrd plce. Insights Img. 2013;4: Wu Z, Mittl S, Kish K, Yu Y, Hu J, Hcke EM. Identifiction of clcifiction with MRI using susceptiility-weighted imging: A Cse Study. J Mgn Reson Img. 2009;182: Mr M, De S, Cortés GL, Cortés IL, Zufiri LO. Clcificciones intrcrneles. Imgen por RM. Intrcrnil clcifictions on MRI. Rdiologí. 2006;48(1): Sumid M, Brkovich AJ, Newton TH. Development of the Pinel Glnd: Mesurement with MR. AJNR Am J Neurordiol.1996;26(L): Deepk SA JB. Intrcrnil clcifictions. J Assos Physicins Indi. 2005;53: Zimmermn A. Age-relted incidence of pinel clcifiction detected y computed tomogrphy. Neurordiol. 1982;142: Mślińsk D, Lure-kmionowsk M, Deręgowski K, Mśliński S. Assocition of mst cells with clcifiction in the humn pinel glnd. Foli Neuropthol. 2010; Kunz D, Schmitz S, Mhlerg R, Mohr A, Stöter C, Wolf K, et l. A new concept for meltonin deficit : On pinel clcifiction nd meltonin excretion. Neuropsychophrmcology. 1999;21(6): Whitehed MT, Oh C, Rju A, Choudhri XAF. Physiologic pinel region, choroid plexus, nd durl clcifictions in the first decde of life. AJNR Am J Neurordiol. 2015;36(3): Doyle AJ, Anderson GD. Physiologic clcifiction of the pinel glnd in children on computed tomogrphy: Prevlence, oserver reliility nd ssocition with choroid plexus clcifiction. Acd Rdiol. 2006;13(7): Rev. Colom. Rdiol. 2017; 28(3): Kendll B, Cvngh N. Intrcrnil clcifiction in peditric computed tomogrphy Neurordiology. 1986;28(4): Kıroğlu et l. Intrcrnil clcifictions on CT. Dignostic Interv Rdiol. 2010; Agrwl PJ, et l. Spectrum of CT nd MR findings in Sturge-Weer syndrome: A cse report. Medicl Journl of Dr. D.Y. Ptil University. 2014;l 7(4): Bron Y, Brkovich AJ. MR Imging of tuerous sclerosis in neontes nd young infnts. AJNR Am J Neurordiol. 1999;(My): Umeok S, Koym T, Miki Y. Pictoril review of tuerous sclerosis in vrious orgns. Rdiogrphics. 2008;28(7):e Arts WFM VDK. Intrcrnil clcified deposits in neurofiromtosis. J Neurol Neurosurg psychitry. 1986; Fortmn BF, et l. Neurofiromtosis Type 1 : A Dignostic Mimicker t CT 1. Rdiogrphics. 2001;21(3): Yilmz N, Unl O, Kiymz N, Yilmz C, Etlik O. Intrcrnil lipoms clinicl study. Clin Neurol Neurosurg. 2006;108: Cvlheiro S, López A, Serr S, Cunh A D, Devnir M, Cost S, et l. Microcephly nd Zik virus: neontl neurordiologicl spects. Child s Nerv Syst. 2016; Ahijit S nd Kr G. Intrcrnil hemorrhge reveling pseudohypoprthyroidism s cuse of Fhr syndrome. Cse Reports Neurolog Med. 2011; Chen X, Lm WWM, Ng K, Fn Y. The frequency nd determinnts of clcifiction in intrcrnil rteries in Chinese ptients who underwent computed tomogrphy exmintions. Cererovsc Dis. 2006;21: Conch T, Moriones AB, True HV. Clcificciones intrcrneles en el TC de urgencis: Mnul pr el residente. Ojetivo docente. 2012; Kln C, Burrows EH, Ch B. Clcifiction in intrcrnil gliomt. Br J Rdiol. 1962;(Septemer): Correspondence Ctlin Wilches Deprtmento de Rdiologí e Imágenes Dignóstics Clínic Rein Sofí Bogotá, Colomi ctlinwilches@yhoo.com Received for evlution: April 28, 2017 Accepted for puliction: June 27,