by Bailey, in1898(1).Routineimagingandhistopa in 1950,andthefirstindexcasewas,fact,described apoplexywascoined byBrougham pituitary The term Arch Metab. Endocrinol 2015;59/3 adenomas(5)anditsrisk in pituitary to 10%oftreated des per100,000person-years (4).PA occursin0.6% 100,000 inhabitants(3)and incidenceof0.17episo PA ~ 6.2 cases per with an estimated prevalence is rare, EPIDEMIOLOGY threatening. asitmayinfactbelife treated, andproperly recognized theconditionmustbe adenoma.Althoughrare, tuitary pi unrecognized cases, apoplexyinvolvesapreviously deficienciesasACTH.Inmost sing pituitary ofconsciousness,besidescau and, even,impairment palsies cranialnerve cause ,visualimpairment, can oftissuevolumewithinthesellarregion increase anabrupt and,asaresult, “sudden attack”inGreek, thenPA frequent is muchmore (2).Apoplexymeans knownassubclinicalapoplexy, hemorrhage, tary and thological evaluationmaydetectasymptomatic pitui P INTRODUCTION be periodicreevaluated. usually donotrecover, regardless thetreatment.Sellar imagingandendocrinologicalfunctionmust glucocorticoidmakes replacementneededinmostcases.Pituitarydeficiencies,onceestablished, tuitary functionisimpairedinmostpatientsbeforeapoplexyand ACTH deficiencyiscommon,which ciousness and/or vision are impaired, despite replacement and support. Pi ,the acutephaseisstillcontroversial. usually bytranssphenoidalroute,isindicatedifcons tarism. Mostcasesimprove withbothsurgicalandexpectantmanagementthebestapproach in surgery. Clinicalpicturecomprisesheadache, visualimpairment,cranialnervepalsiesandhypopitui­ mas. asarterialThere aresomepredisposingfactors , anticoagulanttherapyandmajor chemia and/or necrosis, usually in a . Most cases occur during the 5 Pituitary apoplexyischaracterized bysuddenincreaseinpituitaryglandvolume secondarytois­ ABSTRACT Andrea Glezer diagnosis andmanagement : pathophysiology, life, predominantlyinmalesandpreviouslyunknownclinicallynon-functioningpituitaryadeno Pituitary; apoplexy; pituitary adenoma; apoplexy;pituitary Pituitary; Keywords farction and/or hemorrhage of the . ofthepituitary and/orhemorrhage farction apoplexy(PA) ischaracterizedbyacutein ituitary 1 , Marcello D. Bronstein Arch EndocrinolMetab. 2015;59(3):259-64 1

------not a previously knowncondition(2). Macroadeno not apreviously adenomawas Amongst 60%to80%ofcases,pituitary entity(8). rare PAcols. reviewed inadolescents,avery inmales.Jankoswski and preponderance a discrete per 100person-year(6,7). adenomasis0.2-0.6events non-functioning pituitary VEGF mRNA may be increased inpitui cularization. VEGFmRNA maybeincreased vas (immature) reduction andtumoralabnormal flux tumorblood vascular occlusionduetotumor growth, tood. However, hypothesis involvestumor aproposed pathophysiologyisnotcompletely unders The precise PHYSIOPATHOLOGY (14). Rathke’s cleftcystandsellartuberculoma (13),, cellcarcinoma renal from (11,12),metastasistopituitary, especially been described in non-adenomatous lesions including PA (10). factorassociatedwith nus invasionmaybeaprognostic si (9).Cavernous hasbeenreported microadenomas most susceptibletoapoplexy, apoplexyin nevertheless are mas, especially non-functioningandprolactinomas, Usually, PA occursinthefifth orsixthdecade,with Although PA usuallyoccursinadenomas;ithasalso th decade of ­ ­ ­ 1 (HCFMUSP), SãoPaulo, SP, Brazil of SaoPaulo MedicalSchool dasClinicas,University Hospital andMetabolism, Accepted onMay/29/2015 Received onMay/29/2015 [email protected] –SãoPaulo, SP,05403-000 Brazil 8º andar, bloco3 Rua EnéasdeCarvalho Aguiar, 155, Marcello D. Bronstein Correspondence to: DOI: 10.1590/2359-3997000000047 NeuroendocrineUnit,Divisionof review 259 - - - - -

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. Figure 1. apoplexy (5). Mechanisms contributing totheclinicalpictureinpituitary three serieswithsymptomaticcases,the ratioapople three (18).In and withinthefirstyearahalfoftreatment inmacroprolactinomas, reported frequently was more PA. apoplexy largely used in As , they are Pituitary apoplexy 260 ofPA related somecasereports are rhage (19).There associatedwithhemor more and femalegenderwere patients.Macroprolactinoma inonlythree observed imaging wasdepictedin6.8%andsymptomaticPA was tly, in hemorrhage in368patientswithprolactinomas: recen xy/therapy variedbetween1.2to6.67%.More gulant therapy, andneworalanticoagulants(17). quent (2). Other common risk factors include anticoa themostfre of PA hypertension cases, witharterial agonist therapy, lymphocytic leukemia and head trauma. replacement, tus, sicklecellanemia, tegories oftriggeringfactorshavebeensuggested(16): vasculopathy may occur in apoplectic tumors. Four ca cularization (15).Astheusualtriggerisnotidentified, vas toanabnormal adenomas, whichcouldberelated tumors,especiallyinnon-functioningpituitary tary Hypopituitarism Intrasellar pressure Other riskfactorsincludepregnancy, diabetesmelli Dopamine agonists are considered ariskfactorfor considered Dopamine agonistsare Precipitating factorscanbeidentifiedin about40% Precipitating 4. 3. 2. 1. . Coagulation disturbs: thrombocytopenia, anti Coagulation disturbs:thrombocytopenia, tests, speciallyTRH,GnRHanaloguesuse. pituitary stimulation:provocative Pituitary systemic hypertension. inbloodflow:physicalactivity,Acute increase surgery, radiotherapy, postspinalanesthesia. Vascularreduction: surgery, flux speciallycardiac Hemispheric signs Sudden decrease in thecaliberof (intracavernous as hemiplegia carotid carotid artery portion) and vasospasm necrotic tissueinto the subarachnoid Blood leakageor Leading to chemical increase in space Sudden

Cerebrospinal fluid leakage ------to medical treatment in : three casesonoc three inacromegaly: to medicaltreatment increased pituitary volume secondary to lactotroph hyper tolactotroph volumesecondary pituitary increased also beendescribedinthePA context(25). has is associated withPA, surgery minor laparoscopic described. recently dengue(24)were and hemorrhagic (22). Otheruncommonriskfactorsashighaltitude(23) adenomas dering PA riskinpatientsharboringpituitary consi may be a safer alternative used for prostate four hoursafterthefirstinjection.GnRHantagonistalso within maleandeigthpresented tion, of15cases,14were metabolic activitymaybeinducedbyGnRH(21). intumorcells may causevasospasm;andanincrease levelsbyTRH norepinephrine clear; howeverincreased not with TRHandGnRHstimulation.Mechanismsare associated with extrasellar extension. Most cases were described,with93%macroadenomas docrine testswere (20). lanreotide andfourcasesreceiving treotide are detailed in figure 1. detailedinfigure are health insurance,hadbeenassociatedwithPA (27). (26). surgically treated mostwere no information, adenomasandonewith four non-functioningpituitary ­ twoGH-secre nancy: tenprolactinomas, PA Piantanida and cols. reviewed . during preg bloodflowinducedby pituitary and alsoduetoincreased sixmonthspost-partum, tonormal plasia, whichreturns isariskfactorforPA,Pregnancy duetoan probably Although majorsurgery, surgery, especiallycardiac ofPAIn areview followingGnRHanalogadministra 2012,34casesofPAThrough afteren occurring Mechanisms explainingclinicalmanifestationofPA And finally, socioeconomicfactorssuchaslackof Pressure oncontentsandin brainstem and/or consciousness transmitted to Leading to neural structures reduction Pressure Optical chiasma impairment and compression deficiency Arch Metab. Endocrinol 2015;59/3 ting adenomas, ting adenomas, Neural palsie(III, IV, V and VI nerves) ------Arch Metab. Endocrinol 2015;59/3 NA: notavaiable;NFPA: adenoma. nonfunctioningpituitary Table 1. apoplexy Seriesofpatientswithpituitary migraineandhemorrhagic nous sinusthrombosis, caver other conditionsinclude:midbraininfarction, andbacterialmeningitis; diagnoses are adenoma.Common differential pituitary ofknown history most patientsdonothaveaprevious suspicion isneededtomaketheclinicaldiagnosisas of visual defectsandophtalmoplegia.Ahighdegree is described(28).Mostpatientscomplainofheadache, after theonsetofapoplexy, althoughasubacutecourse Classically, hourstotwodays symptoms evolvefrom DIAGNOSIS ANDMANAGEMENT insipidus LH/FSH TSH ACTH deficiency % hormone Pituitary surgery recovered after visual acuity Visual fielddeficits/ Predisposing factors Ophtalmoplegia Visual defects Headache Symptoms % Operated Mean age(yr) Male/female N Patients NFPA Adenoma type% and cols., 1993 (32) 95%/88% Bills DC 25/12 56.6 11 64 89 82 78 64 95 36 37 17 52 one witharterial mellitus, oneon MacCagnan P 2 withdiabetes , major surgery, hypertension, chronic renal radiotherapy, and cols., 1995 (33) one witha one with one with pituitary pituitary failure 62% 100 7/5 41 33 25 83 66 43 12 5 - - - Randeva HS contraceptive hypertension, oral pills, 9% 26% arterial and cols., 1999 (34) 86%/76% on aspirin therapy 21/14 49.8 14% 5.5 43 43 58 69 71 97 31 35 61 6 ­ hypertension 33% arterial and cols., 2004 (30) 57%/NA Ayuk J 20/13 75 60 78 46 82 97 15 52 33 24 6 - in a Rathke’s cyst and . Itisim inaRathke’scystandaneurysms. infarction cases, respectively (29). cases, respectively MRIidentified100%and88%of 21% ofcases,whereas in tumorin93%andhemorrhage identified pituitary series,aCTscan lesions.Inaretrospective of pituitary scan iseasiertoobtain,itlesssensitivefordiagnosis sion. Although cranial computedtomography (CT) detailedintable1. patients andare atarateof7.4%. aneurysms cerebral adenomasco-existwith thatpituitary tostress portant imaging is required to identify a pituitary le toidentifyapituitary Brain imagingisrequired thanten includemore Eight seriesintheliterature 2 2 headtrauma, Lubina and treatment, 1 cols., 2005 anesthesia 81%/NA general 27/13 51.2 (35) 79 54 40 31 40 61 63 34 40 63 8 hypertension, Bujawansa Bujawansa 20% arterial and cols., 2014 (36) 80%/NA three on warfarin 52.7 72.7 11.5 47.2 52.4 77 36 87 22 55 82 3 Jho andcols., 2014 (37) 69/40 35.8 39.4 101 109 87 51 Pituitary apoplexy cols., 2015(38) on anticoagulant 12.6% diabetes mellitus, 10.3% two aftermajor partum period, 93.3%/94.4% hypertension, pregnant and three inpost 39% arterial therapy, one Singh and surgery surgery 57/30 63.6 62.7 13.2 33.3 89.7 50.9 29.5 23 60 61 87 39 261 - -

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. Pituitary apoplexy 262 toin than 4appeared equaland more 10, andascore 0to ve palsiesandGlasgowComa Scale,rangingfrom calculated usingvisualacuity, visualdefects,cranial ner inUK,PA was days ofsymptom.Inadepartment score withinthefirstseven if performed visual improvement withahigherrateof dications ofsurgical intervention, in withclinicalmanagementare ration notimproving deterio andneurological impairment team (2).Visual amultidisciplinary from should bemadebyexperts (29,32). shed, usuallydonotrecover, thetreatment regardless deficiencies,onceestabli eded inmostcases.Pituitary ne replacement common, whichmakesglucocorticoid apoplexyandACTHdeficiencyis most patientsbefore in functionisimpaired or withoutsurgery. Pituitary spontaneously,(2). Ophtalmoplegiacanresolve with usually within sevendaysafter the apoplectic event obtainedwithsurgical decompression, readily is more ofvisualfields and acuityimpairment Recovery pport. su andelectrolyte replacement despite glucocorticoid impaired, indicated if consciousness and/or vision are that surgery, is usuallybythetranssphenoidalroute, evidence(2,29).However,for strong seemsintuitive a randomizedtrialcomparingbothstrategiesisneeded analgorithmforPA UK,proposed from management, (28).Althoughguidelines, astheone is controversial intheacute phase approach and themostappropriate withbothsurgical andexpectantmanagement improve administration.MostPA cases ces andcorticosteroid disturban ofelectrolyte namic stabilization,correction (2). encountered pidus israrely Transient secretion. hormone diabetesinsi antidiuretic orinappropriate tohypocortisolism can besecondary inupto40%ofcases, surgery. observed , after function recovery ofpituitary a lowerprobability exhibit (14,28,31). Patientswithlowlevelsofprolactin in75%ofcases 70%, TSHin50%andgonadotrophin cies occurinnearly80%ofpatients:ACTHupto deficien 6hours(30).Anteriorpituitary nously every 50 mgintrave 8 to16mgperdayorhydrocortisone edemaonparasellarstructures: control mended andasupraphysiologicaldoseisindicatedto isrecom replacement ning condition,glucocorticoid as hypopituitarism.AsACTHdeficiencyislife-threate aswell andcorticotropinoma, noma, somatotropinoma adenomasincluding prolacti pituitary nose secreting Hormonal pituitary evaluation is required to diag evaluation is required pituitary Hormonal The decision to manage conservatively orsurgically The decisiontomanageconservatively after PA diagnosisishemody The firstintervention ------be observed withMRI.Sphenoidsinusmucosathick be observed progressive increase insignalonT increase progressive CT scan. It is difficult to differentiate para PA from to differentiate CT scan.Itisdifficult inan uncontrasted intrasellar andsuprasellarregions isdepictedin days,hyperdensity thefirstthree Within Imaging follow-up apoplexy. forpatientswithpituitary quired surgically (37). treated patients (101)were Themajorstudybiasisthatmost medical treatment. ofsignificantclinicalcomorbiditiesfavor the presence Rathkecleftcystsand hemorrhagic that prolactinomas, (grade5).Theyalsoobserved be submittedtosurgery racteristics isusefulinidentifyingpatientswhoshould considering clinical and imaging cha score proposed thors evaluated109casesofPA concludingthattheir visual deficitsoralowGlasgowComaScale.Theau andgrade5for 3 forheadache,grade4ocularparesis matic, grade2symptomsduetoendocrinopathy, grade forPA: anotherscore cols. proposed grade1asympto (2).Jhoand surgery fluence themanagementtowards disappearance is common, avoiding additional treat MRI (29). and hypointenseonT1 hyperintenseonT2 imaging canbedetectedashypodensitybyCT crosis changes inPA findings.Ne bytime,forhemorrhagic Tableof latesubacutehemorrhage. 2summarizesMRI sediment,issuggestive bloodremnants ponding tored bin and the lower layeriso-hypointenseonT1corres toextracellularmeta-hemoglo on T1,corresponding ages (39,40). inbothT issignalincrease there phase, sented byathinperipheralrim.Inthechronic signalonT geneous increased (between 7 ening issuggestiveofPA intheearlyhours.Subacutely ally inthefirstweek,anisointensityonT hoursafter apoplexy.perior duringthefirstthree Usu abscess orcysticdegeneration.Incontrast,CTissu minishes andthelesioncouldbemisdiagnosedasan fades,CTsensitivitytodiagnosePAhemorrhage di phasesof inthesubacuteand chronic As hyperdensity usingCT, specific. andMRIismore sellar After gadolinium,aperipheralenhancementisrepre scans andahypointensityonT Long-term endocrineandimagingfollow-upisre Long-term Using serial sellar MRI, tumor reduction andeven Using serialsellarMRI,tumor reduction mass,hyperintense Fluid debrislevelsinapituitary th and14 th days), there isfocalorhetero days),there Arch Metab. Endocrinol 2015;59/3 1 -weighted scans,anda 2 1 -weighted imagescan andT 2 -weighted images. 2- weighted im 1 -weighted ------Arch Metab. Endocrinol 2015;59/3 mustbe secretion adenomas,hormonal tioning pituitary For func isrequired. replacement hormone Appropriate Endocrinological follow-up hyperintense lesioninseeing T apoplexy:Figure 3.SellarMRIdepictingsignsofasubacutepituitary a noncontrasted T patients: (a): a hyperintense lesion impinging optical chiasm in apoplexyintwo Figure 2.SellarMRIdepictingsignsofaacutepituitary then, biannual(2). ter apoplexy, annuallyinthefollowingfiveyearsand normal. GHandIGF-1levelswere rum 3.Afterapoplexy, isdepictedinfigure acromegaly se 2andasubacute picted infigure PA inapatientwith vative management(31). afterconser 6% ofpatientsandthisriskisnotincreased tary. hasbeendescribedin However, tumorrecurrence pitui emptysellaorevennormal empty sella,partially imaging shows ment in most cases.Inthelong-term, Table 2. apoplexy MRIfindingsinpituitary T 1 apoplexy phase -weighted scan. T T MRI scan can be performed three tosixmonthsaf three MRI scancanbeperformed A sellarMRIdepictingsignsofanacutePA isde 2 1 Pituitary Pituitary -weighted -weighted scans scans 1 -weighted scanand(b): aperipheralrimincontrasted (until 7 Hypointense Isointense Acute th day) 1 ) and T -(a) Increase insignal (7 hyperintense th Subacute to14 Hypo or 2 -(b) weightedscans. th day) Chronic (more than 15days) Hyperintense Hyperintense ------remain highafterapoplexy.remain follow-upisindi Long-term levelscouldbelow,also evaluated:hormonal or normal pituitary functiontests.Treatment consistsofsubstitu pituitary andothersystemicsurgeries anddynamic sion, cardiac with trauma,anticoagulationtherapy, hyperten arterial andcouldbeassociated uncertain physiology remains forthediagnosis.Apoplexypatho (MRI) iscrucial imaging nonfunctioning. Cranialmagneticresonance apoplexy, althoughinsomeseriesmosttumorswere atriskof adenomatypesare of ~50years.Allpituitary withameanage slight maletofemalepreponderance isa levelofconsciousness.There sies, anddecreased , visual disturbances, blindness, ocular pal includes acuteheadache, meningismus, and PA evolvesinhourstotwodaysandthecondition CONCLUSION (2). to eightweeksafterapoplexyisrecommended four Areevaluation cated toidentifytumorrecurrence. 12. 11. 10. 9. 8. 7. 6. 5. 4. 3. 2. 1. REFERENCES cases. insevere by and sellar decompression tion therapy with steroids

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