Update On The Natural History Of Infratentorial Cavernous .
378M. Gorgan et alNatural history of infratentorial cavernous malformationsUpdate on the natural history of infratentorial cavernousmalformationsM. Gorgan, Angela Neacsu, Narcisa Bucur, V. Pruna, A. Giovani,Aura Sandu, Adriana DediuFirst Neurosurgical Clinic, Fourth Neurosurgical Department, Clinic EmergencyHospital “Bagdasar-Arseni”, BucharestAbstractInfratentorial cavernous malformationsare still a source of serious controversies inneurosurgery and their natural history andtreatment are intensely debated inliterature. Recent studies suggest s have a more aggressiveclinical outcome than the supratentorialones (the risk of hemorrhage isapproximately 30 times that of thesupratentorial cavernomas) The optimaltherapeutic approach of infratentorialcavernomas need a good understanding ofthe natural history and also thecharacteristics that may influence theassociated neurological risk, like the patientstatus at admission, the localization and thegenetics of the malformation. Many studieshave been published in the last decades toenlight the clinical aspects and the naturalhistory of these vascular malformations.The purpose of this analysis is to make aliterature review of the morbidity riskassociated to cavernous malformations andtheir influence on the treatment plan.Keywords: natural history, infratentorialcavernomas, risk of hemorrhageIntroductionEven if the first account of cavernomasurgery dates back to 1928 when Dandyevacuated a brain stem hemorrhage,resulted from a ruptured cavernoma studieson the natural history and management ofthese lesions appeared after 1980.Cavernous malformations are composedof a compact mass of sinusoidal-type vesselsimmediately in apposition to each otherwithout any recognizable interveningneural parenchyma, delimited only by arow of endothelial of cells surrounded byconjunctive tissue. They may reach aconsiderable size and usually are round orlobulated. They can be classified on variouscriteria: number, location, type ofdevelopment, MRI aspect, etc. The mostused classification is: sporadic form, withunique lesions and familial formcharacterized by multiple lesions and afamily history.The familial type of disease is found in20-30% of the patients with cavernousmalformations. According to the time ofappearance cavernomas can be congenital,present at birth (all cavernomas wereconsidered congenital till 1990) and denovo, developed after birth, spontaneous orpostiradiation.According to localization infratentorialcavernomas are classified in cerebellar(Figure 2) and brainstem cavernomas(Figure 1), this classification beingextremely important in the therapeuticplanning.
Romanian Neurosurgery (2011) XVIII 4: 378 - 389379CADBEFigure 1 Pontin cavernoma, unverified operator in apatient found incidentally 35 years after a caraccident: A, B – CT scan; C ,D, E - MRI T2 axialsection, T1 sagittal and T1 coronary section in thesame patient with pontin cavernoma (PDS).
380M. Gorgan et alNatural history of infratentorial cavernous malformationsCADBEFigure 2 Left cerebellar cavernoma (P.C., men, 18years old): A, B – CT scan; C, D, E - MRI T2 axialsection, T1 coronary and T1 sagittal section.
Romanian Neurosurgery (2011) XVIII 4: 378 - 389Brainstem cavernomas are considered aspecial pathology given the risk ofhemorrhage that is 30 times that ofcavernomas elsewhere located, and aventricular cavernomas (Figure 3)was reported in literature to account for 2,5to 10,8% of brain cavernomas.CADBE381
382M. Gorgan et alNatural history of infratentorial cavernous malformationsFGHFigure 3 IV ventricle cavernoma operated (63 yearsold, sex M): A, B – CT scan; C, D, E, F – brain MRI(N K); G, H – postoperative CT scanEven small changes in brainstemcavernomas silent on MRI can cause majorneurological deficits (23, 39). In the naturalhistoryofbrainstemcavernomascontradicting characteristics have beenreported. Some studies reported a benigntumor behavior (24), with a bleeding rate of2.46% per year and a rebleeding rate of5,1% per year, while other studies (40)reported a malignant natural history with arate of rebleeding of 5% per year, and arebleeding rate of 30%. The correct clinicalevaluation and treatment of infratentorialcavernomas is based on hemorrhagic andneurological associated risk understanding,and also the factors that influence this risk.This study is aimed to review theknowledge on the natural history ofinfratentorial cavernomas and to make itready usable for the neurosurgeon intreating these patients.MethodsThe literature data was selected andsorted from PubMed, using the ion”, “cavernoma”, ��hemorrhagic risk”, “neurologic risk”. Thisreview was limited to studies published inenglish. The studies that n, risk of hemorrhage andprognostic factors (age, sex, dimension, andgenetics) were investigated.EpidemiologyThere is no reliable study to offer preciseinformation about the incidence and theprevalence of cavernomas. Based oncadaveric studies and IRM images, theprevalence was estimated 0,5% - 0,7% (15,43). The incidence of cavernomas was
Romanian Neurosurgery (2011) XVIII 4: 378 - 389estimated to 0,4% and 0,9%, accounting for8% - 15% of all intracranial vascularmalformations. (15, 22, 32, 39). There is nogender difference even if some studiesshowed a small difference in favor ofwomen (1, 23, 35, 40, 44, 48, 49). Up to25% of cavernomas appear in pediatricpopulation. More than 60% are superficial,30% are profound (brainstem, cerebellarnuclei basal ganglia and thalamus) and 3%are located in spinal medulla. Multiplecavernomas appear in 90% of familial formsand in approx. 25% of sporadic forms (12,26). In average, 20% of cavernomas appearin posterior cranian fossa and 80% aresupratentorial. The frequency of brainstemcavernoma is reported to be somewherebetween 9% - 35% (24, 40). The averagesize of cavernomas is between 15 - 19 mm(22, 43). Only 10% of lesions remainunmodified in time; 35% grow and 55%shrink (12). This dynamic is related torecurrent bleeding and resorbtion of bloodproducts or to changes in osmotic pressure(52). More and more authors agree to thepresence of a subgroup of de novocavernomas. (36).They can be frequently associated withvenous angiomas (Figure 4), thisrelationshipismorefrequentininfratentorial types (18, 40). The largepercent of associated lesions determinedsome authors to consider that the venousanomaly determines the cavernomaformation. (the affected venous drainagecan take to capillary channels dilation). Thistheory is sustained by a rare observation:the cavernoma reccurency post resectionwas not reached in patients with associatedDVA. (51).ABC383
384M. Gorgan et alNatural history of infratentorial cavernous malformationsDEFFigure 4 Appearance MRI on three years after totalresection of a cavernoma of the vermis andhighlighting the marked increase in size of the threeright cerebellar hemisphere cavernomas, placedaround the venous angioma. Cavernomas wasresected surgical and the angioma was treatedconservatively: A – T1 axial section, B, C, D, E, - T2gradient echo axial section.PathophysiologyCavernomas pathophysiology stands in aslow degradation of blood in cerebralparenchyma resulting in a hemosiderinring, and perilezional gliosis. Almost allcavernous malformations have signs ofrecent hemorrhage. In contrast with aspontaneous intracerebral hemorrhageassociated with hypertension, little isknown about the physiopathology ofcavernoma bleeding.Most of the microhemorrhages appearintralezional and this is the ge is asymptomatic. Thesituation of extralezional bleeding from acavernoma is rare, it is cause for aintraparenchimal hematoma, usually beingnonfatal, given the diminished blood flowand pressure inside the cavernoma. (46).Infratentorial cavernomas have a bleedingrate bigger than the supratentorial ones butthe cause. Mechanisms of cavernomasvolume growth (11): Acute massive hemorrhage withsudden volume growth and mass effect orrepeated small bleedings and thrombosistaking to a growing cystic lesion (41); Chronic hemorrhage from thin walledvessels, with repeated reendotelisation, ofthe bleeding cavity, angiogenesis inside thedeveloped hematoma, and perilezionalmatrix growth (30, 45); Intraluminalthrombosiswithrecanalization and organization (42); Angiogenesis proliferation with newcapillaries as a phenomenon of on by coalescence (30); Hemorrhage by adjacent cerebralparenchymal vessels erosion (33); Imunohistochemicaldemonstratedproliferation (37,47);
Romanian Neurosurgery (2011) XVIII 4: 378 - 389 Nidus growth by new cavernsformation (17, 27); Vascular smooth muscle proliferation(3);PresentationPatients with cavernomas have a richsymptomatology with onset between 30 50 years old. Bleeding inside the cavernomaand the compressive effect according tolocalization and dimensions are themechanisms of clinical signs. Thehemorrhage determines neurologic deficitsdepending on the location of the lesion, forexample a bleeding from a brainstemcavernoma can result in cranial nervedeficits, like diplopia, facial palsy, vertigo,ophtalmoplegia, tinnitus, hearing loss,dysarthria and dysphagia.Brainstemsyndromes even as a consequence ofischemic lesions can be elicited also bycavernomas, according to their localization:Wallenberg syndrome, Millard-Gublersyndrome, Weber syndrome, BenediktsyndromeorParinaudsyndrome.Cerebellar hemorrhages in cerebralpeduncles or on cerebellar can result inataxia or nistagmus, but also cerebellarmutismwasdescribed.Cerebellarhemorrhage can also result in IV’thventricle obstruction and hydrocephalus.Important hemorrhage in brainstem orpons cause loss of consciousness, coma andeventually death. The pons is a well-knownsite of fatal intracranian hemorrhage. Allthese neurological deficits can result fromcavernomas through their compressiveeffect without bleeding, having a slowlyprogressive course that can lead todiagnostic confusion, without a completeimagistic they mimic a clinical setting ofmultiple sclerosis or pontine glioma (34).Headache is a usual but nonspecific sign ininfratentorial cavernomas. It is a very rare385situation for the brainstem cavernomas toproduce seizures. The frequency ofasymptomatic cavernomas is not preciselydefined but according to Zabramski (52)and Brunereau (9, 10) it seems to be evenmore than 40%.Natural historyAt the beginning of 1990 (once the MRIbecame widely available) the hemorrhagicrisk associated with brain cavernoma, wasmore and more accepted. (15).The hemorrhagic pattern presents agreat variability with many terms thatdefine the hemorrhagic event in literature(1, 2, 6, 15, 16, 23, 38, 41, 43, 44, 54).Hemorrhage is the main problem also froma clinical and a therapeutic point of view.Even if this problem seems facile somehypothesis are wrong. The problem startswith a definition for hemorrhage and endsin particular responses for every patient. Onone side, the hemorrhage can be definedbased on clinical status: de novo or suddenonset of new symptoms in a cavernomapatient, resulted from a rebleeding episode.There are many descriptions and manyterms used in literature to define ahemorrhage associated with cavernoma:clinical significant cavernoma; orrhage, intralezional hage, subclinical hemorrhage, etc.(1, 20, 23, 8). Still the problem ofhemorrhage in cavernomas is a reason fordebate regarding the risk of hemorrhageand the rate of rebleeding in patients withcavernomas. Most of the estimates take intoaccount the fact that cavernomas are presentat birth and they base the appreciation ofthe risk of hemorrhage and risk ofrebleeding on this supposition.
386M. Gorgan et alNatural history of infratentorial cavernous malformationsDel Curling et al. (15) and de Robinsonet al. (43) were the first to calculate theannual rate of hemorrhage, between 0,25%and 0,7% / year.Hemorrhage risk factorsHemorrhagiconset(hemorrhagicpresentation) has a negative impact on thenatural history of cavernoma. Patients witha hemorrhagic onset have a higher risk ofrebleeding than patients with some othersymptomaticonsetoraccidentallydiagnosed, 22,9 per year, compared to0,39% per year (1, 23). Other studies (31,35) did not recognize the presence ofhemorrhage as an independent risk factor,butobservedthatpatientswithhemorrhagic or non-hemorrhagic onsetassociated with focal neurological deficithad higher rebleeding rates than thosewithout neurological deficits. (8,9%compared to 0,4% /patient-year). Aspontaneous drop off of the rebleeding riskafter approximately 2 years after ahemorrhagic episode was remarked, the socalled “ temporal clustering” phenomenon(5,50).Anatomic location. A higher rate ofsymptomatic recurrent hemorrhage wasreported related to infratentorial locationthan in supratentorial location (39),3,8%/patient/yearcomparedto0,4%/patient/year, also a higher incidence cationcomparedtosupratentorial ones (44). Patients withsupratentorial cavernomas have a lowprobability of fatal hemorrhage, most of thepatients having a complete or almostcompleterecovery after the firsthemorrhagic episode, but this situation isnot true for infratentorial location where ahemorrhage, especially in pons can be fatal.In Fritschi’s (17), series of 139 brainstemcavernomas a high rate of symptomatichemorrhage of 2,7% /patient/year and 21%/patient/year rebleeding ratewasencounted.In the series published by Porter (40),the symptomatic hemorrhage rate and thesymptomatic rebleeding rate are ear.Female sex. Some authors (4, 40, 43)reported a significant growth of thehemorrhage rate in women, but in most ofthem the gender difference wasn'tsignificant. (17, 23, 39).De novo development. Initially allcavernomas were thought to be congenital.There are many proofs of de novocavernoma development. Radiotherapy isone of the factors in favor of de novocavernoma formation (36), along withgeneticfactors,viruses,hormonalinfluences during pregnancy, and localdissemination at biopsy. De novocavernomaformationwasrecentlyconfirmed based on MRI studies in patientswith familial form. Even more studiescounted the de novo cavernoma formationincidence between 0,1 and 0,6 new lesions/patients/year(21,25,52).Thisphenomenon is much more frequent infamilial than in sporadic form, respectively27,5%-30% of the patients with familialform have de novo cavernomas while only4,1% of patients with sporadic form developde novo cavernomas with time (25, 26,41).Size Dynamics. De novo cavernomaformation isn't the sole dynamic aspect ofcavernomas, they can also report importantgrowth with time. The best study to provethe dynamics of cavernomas is that ofClatterbuck (12), who observed 68 patientswith 114 cavernomas, on MRI on anaverage period of 3,7 years. He concluded
Romanian Neurosurgery (2011) XVIII 4: 378 - 389that 22% of lesions were stable, 43%reported growth and 35% shrinkage. Thereis no study so far to associate the growth ofcavernomas with the risk of hemorrhage.Inherited form. Even if most of thecavernomas are considered to be sporadic,more and more familial cases were observedin the last two decades. These cases have anautosomal dominant inheritage, and aremost common in hispanic population.Recent studies showed at least 3 distinctgenes related to the familial form of disease,two of them being precisely located.The first gene is CCM1 (cavernouscerebral malformation 1) and is located onchromosomal 7 at 7q11.2-q21 locus.Another known gene is KRIT1, namedafter the corresponding protein GeneCCM1 is present in 40% of familialcavernomas. The precise function ofKRIT1 is unknown it is probably a tumorsuppressor (13, 14, 19, 28, 53). The secondgene is CCM2. This is located at 7p15-p13and it codifies the protein malcaverin.About 20% of familial forms may be relatedto a mutation in CCM2. The third geneidentifiedisCCM3,locatedonchromosome 3 at 3q. The function of thisgene and its association with cavernoma isstill under research. All the 3 genes seem tohave implications in angiogenesis. As from2004 January tests for CCM 1 mutationsare available and in short time tests forCCM 2 will be available. Recent studiessuggest the presence of another gene (7,29). Also genetic etiologies weredemonstrated in familial forms in 70% ofcases the genetic influence is yet to beestablished in sporadic forms. Sporadicforms can be caused by a loss of function ofCCM1 in heterozygotes. The familial formmay influence the risk of hemorrhage;given the multiple cavernomas and the high387de novo formation rate, in spite of the factthat no higher hemorrhagic rate has beenidentified per lesion.Analyzing the literature data onhemorrhagerelatedtobrainstemcavernoma we can conclude: patients with brainstem cavernomahave a significantly higher risk ofhemorrhage of 5%/year (40), even if someauthors found smaller rates (24), of only2.46%/year; the rate of rebleeding after asymptomatic hemorrhage is 30% per year(40); the rate of bleeding is not related withpatients gender (1,35,43); young age (under 35 years) seems to berelated to a higher rate of bleeding (24); cavernomas with dimensions of at least10 mm have a higher risk of bleeding (24) morbidityrateinbrainstemcavernomas is 8% (24).ConclusionsDecision making in infratentorialcavernomas treatment is strictly related tothe surgical morbidity and the risks in thenatural history of the disease. Prospectivedata in literature to predict the evolution forevery individual patients are lacking so far.A metaanalysis over a long period of time isrequired to elucidate the natural history ofbrainstem cavernomas and to identify thecavernomas with high potential ofneurologic deficits. A good understandingof the natural history provides the surgeonthe ability to evaluate the relative riskassociated to every treatment method. Forinfratentorial cavernomas, the analysis ofthe relative risk is very difficult given thesparse cases reported in literature and thestatistical analysis that limits any. Inaddition, any reported case has an
388M. Gorgan et alNatural history of infratentorial cavernous malformationsindividual variability like the clinical andneurological status, age, associated disease,accessibilityaccordingtolocation.Moreover the experience that theneurosurgeon has in treating these lesions iswhat matters.References1. Aiba T, Tanaka R, Koike T, Kameyama S, Takeda N,Komata T: Natural history of intracranial cavernousmalformations. J Neurosurg 1995, 83:56–592. Awad IA: Cavernous malformations and epilepsy, inAwad IA, Barrow DL (eds): Cavernous Malformations.Park Ridge, AANS, 1993, 49–633. Awad IA, Robinson JR, Mohanty S, Esters ML:Mixed vascular malformations of the brain: clinical andpathogenetic considerations. Neurosurgery 1993, 33:179-1884. Awad I, Jabbour P: Cerebral cavernousmalformations and epilepsy. Neurosurg Focus 2006,21:1e75. Barker FG II, Amin-Hanjani S, Butler WE, Lyons S,Ojemann RG, Chapman PH, et al.: Temporalclustering of hemorrhages from untreated cavernousmalformations of the central nervous system.Neurosurgery 2001, 49:15–256. Barrow DL, Krisht A: Cavernous malformations andhemorrhage, in Awad IA, Barrow DL (eds): CavernousMalformations. Park Ridge, AANS, 1993, 65–807. Bergametti F, Denier C, Labauge P, Arnoult M,Boetto S, Clanet M, et al.: Mutations within theprogrammed cell death 10 gene cause cerebralcavernous malformations. Am J Hum Genet 2005,76:42–518. Biller J, Toffol GJ, Shea JF, Fine M, Azar-Kia B:Cerebellar venous angiomas. Arch Neurol 1985,42:367–3709. Brunereau L, Labauge P, Tournier Lasserve E,Laberge S, Levy C, Houtteville J: Familial form ofintracranial cavernous angioma: MR imaging fi ndingsin 51 families. French Society of Neurosurgery.Radiology 2000a, 214:209–21610.Brunereau L, Levy C, Laberge S, Houtteville J,Labauge P: De novo lesions in familial form of cerebralcavernous malformations: clinical and MR features in29 non-Hispanic families. Surg Neurol 2000b,53(5):475–48211.Ciurea A.V., Coman T.C., Gambardella G.:Actualităţi în cavernoamele intracraniene, EdituraUniverstară “Carol Davila”, Bucureşti, 2005, 41-4612.Clatterbuck RE, Moriaritiy JL, Elmaci I, Lee RR,Breiter SN, Rigamonti D: Dynamic nature of cavernousmalformations: a prospective magnetic resonanceimaging study with volumetric analyses. J Neurosurg2000, 93:981–98613.Craig HD, Gunel M, Cepeda O, et al. Multilocuslinkage identifies two new loci for a mendelian form ofstroke, cerebral cavernous malformation, at 7p15-13 and3q25.2-27. Hum Mol Genet. Nov 1998, 7(12):1851-8.14.Davenport WJ, Siegel AM, Dichgans J, Drigo P,Mammi I, Pereda P, Wood NW, Rouleau GA: CCM1gene mutations in families segregating cerebralcavernous malformations. Neurology 2001, 56:540–54315.Del Curling O, Kelly DL, Elster AD, Craven TE: Ananalysis of the natural history of cavernous angiomas.JNeurosurg 1991, 75:702–70816.Ferroli P, Sinisi M, Franzini A, Giombini S, SoleroCL, Broggi G: Brainstem cavernomas: long-term resultsof microsurgical resection in 52 patients. Neurosurgery2005, 56:1203-121417.Fritschi JA, Reulen HJ, Spetzler RF, Zebramski JM:Cavernous malformations of the brainstem. A review of139 cases. Acta Neurochir 1994, 130:35-4618.Forsting M, Wanke I: Developmental VenousAnomalies, IN: Intracranial Vascular Malformations andAneurysms, Springer 2007, 1-1819.Gaetzner S, Stahl S, Sürücü O et al: CCM1 genedeletion identified by MLPA in cerebral cavernousmalformation. Neurosurgical Review, 2007, 30(2):15516020.Karlsson B, Kihlstroem L, Iindquist C, Ericson K,Steiner L: Radiosurgery for cavernous malformations. JNeurosurg 1998, 88:293–29721.Kattapong VJ, Hart BL, Davis LE: Familial cerebralcavernous angiomas: clinical and radiologic studies.Neurology 1995, 45:492–497,22.Kim DG, Park YG, Choi JU, Chung SS, Lee KC: Ananalysis of the natural history of cavernousmalformations. Surg Neurol 1997, 48:9–1823.Kondziolka D, Lunsford LD, Kestle JR: The naturalhistory of cerebral cavernous malformations. JNeurosurg 1995, 83:820–82424.Kupersmith MJ, Kalish H, Epstein F, Yu G,Berenstein A, Woo H, Jafar J, Mandel G, De Lara F:Natural history of brainstem cavernous malformations.Neurosurgery 2001, 48:47–5325.Labauge P, Brunereau L, Levy C, Laberge S,Houtteville JP: The natural history of familial cerebralcavernomas:a retrospective MRI study of 40 patients.Neuroradiology 2000, 42:327–33226.Labauge P, Brunereau L, Laberge S, Houtteville JP:Prospective follow-up of 33 asymptomatic patients withfamilial cerebral cavernous malformations. Neurology2001, 57:1825–182827.Little JR, Awad IA, Jones SC, Ebrahim ZY: Vascularpressure and cortical blood flow in cavernous angiomasof the brain. J Neurosurg 1990, 73:555-559
Romanian Neurosurgery (2011) XVIII 4: 378 - 38928.Liquori CL, Berg MJ, Siegel AM, et al. Mutations ina gene encoding a novel protein containing aphosphotyrosine-binding domain cause type 2 cerebralcavernous malformations. Am J Hum Genet. Dec 2003,73(6):1459-64.29.Liquori CL, Berg MJ, Squitieri F, Ottenbacher M,Sorlie M, Leedom TP, et al.: Low frequency ofPDCD10 mutations in a panel of CCM3 probands:potential for a fourth CCM locus. Hum Mutat 2006,27:11830.Maraire JN, Abdulrauf SI, Berger S, Knisely J, AwadIA: De novo development of a cavernous malformationsof the spinal cord following spinal axis radiation. Casereport. J Neurosurg 1999, 90:234-23831.Mathiesen T, Edner G, Kihlström L: Deep andbrainstem cavernomas: a consecutive 8-year series. JNeurosurg 2003, 99:31–3732.McCormick WF, Nofzinger JD: “Cryptic” vascularmalformations of the central nervous system. JNeurosurg 1966, 24:865–87533.Michelson WJ: Conservative treatment. In: Awad IA,Barrow DL (eds): Cavernous malformations. AANS,Park Ridge, 1993, 81-8534.Ming X, Gonzales C, Burrowes D, Lastra C,Antunes N: Cavernous angioma of the brain stemsimulating diffuze pontine glioma. J Child Neurol.2001, 16:614-61535.Moriarity JL, Wetzel M, Clatterbuck RE, Javedan S,Sheppard JM, Hoenig-Rigamonti K, et al.: The naturalhistory of cavernous malformations: a prospective studyof 68 patients. Neurosurgery 1999, 44:1166–117336.Nimjee SM, Powers CJ, Bulsara KR: Review of theliterature on de novo formation of cavernousmalformations of the central nervous system afterradiation therapy.Neurosurg Focus 2006, 21(1)37.Notelet L, Houtville JP, Khoury S, L echevalier B,Chapon F: Proliferating cell nuclear antigen (PCNA) incerebral cavernomas: an immunocytochemical study of42 cases. Surg Neurol 1997, 47:364-7038.Otten P, Pizzolato GP, Rilliet B: 131 cases ofcavernous angiomas (cavernomas) of the CNS,discovered by retrospective analysis of 24,535 autopsies.Neurochirurgie 1989, 35:82–8339.Porter PJ, Willinsky RA, Harper W, Wallace MC:Cerebral cavernous malformations: Natural history andprognosis after clinical deterioration with or withouthemorrhage. J Neurosurg 1997, 87:190–19740.Porter RW, Detwiler PW, Spetzler RF, Lawton MT,Baskin JJ, Derksen PT et al.:Cavernous malformationsof the brainstem: experience with 100 patients. JNeurosurg 1999, 90:50–5841.Pozzati E, Acciarri N, Tognetti F, Marliani F,Giangaspero F: Growth, subsequent bleeding, and de389novo appearance of cerebral cavernous angiomas.Neurosurgery 1996, 38:662-67042.Rigamonti D, Hadley MN, Drayer BP, Johnson PC,Hoening-Rigamonti K, Knight JT, Spetzler RF:Cerebral cavernous malformations. Incidence andfamilial occurrence. N EnglMed 1998, 319:343-34743.Robinson JR, Awad IA, Little JR: Natural history ofthe cavernous angioma. J Neurosurg 1991, 75:709–71444.Robinson JR, Awad IA, Magdinec M, Paranandi L:Factors predisposing to clinical disability in patientswith cavernous malformations of the brain.Neurosurgery 1993, 32:730–73645.Scott BB, Seeger JF, Schneider RC: Successfulevacuation of a pontine hematoma secondary to ruptureof a pathologically diagnosed „cryptic” vascularmalformation. Case report. J Neurosurg 1973, 39:10410846.Shiu-Jau Chen et al: Cavernoma of the CentralNervous System: Surgical experience in the magneticresonance imaging era; Acta Neurol Taiwan 1997,6:171-17847.Sure U, Butz N, Schlegel J, Siegel A, Mennel HD,Bien S, Bertalanffy H: Endothelial proliferation,neuroangiogenesis and potential de novo generation ofcerebral vascular malformations. J Neurosurg 2001,94:972-97748.Vaquero J, Leunda G, Martínez R, Bravo G:Cavernomas of the brain. Neurosurgery 1983, 12:208–21049.Voigt K, Yasargil MG: Cerebral cavernoushaemangiomas or cavernomas. Incidence, pathology,localization, diagnosis, clinical features and treatment.Review of the literature and report of an unusual case.Neurochirurgia (Stuttg) 1976, 19:59–6850.Wang CC, Liu A, Zhang JT, Sun B, Zhao YL:Surgical management of brain-stem cavernousmalformations: report of 137 cases. Surg Neurol 2003,59:444–45451.Wurm G, Schnizer M, Nussbaumer K, Wies W, HollK: Recurrent cryptic vascular malformation associatedwith a developmental venous anomaly. Br JNeurosurg.2003, 17(2):188–19552.Zabramski JM, Wascher TM, Spetzler RF, JohnsonB, Golfinos J, Drayer BP, Brown B, Rigamonti D,Brown G: The natural history of familial cavernousmalformation: results of an ongoing study. J Neurosurg1994, 80:422–43253.Zhang J, Clatterbuck RE, Rigamonti D, Dietz HC:Mutations in KRIT1 in familial cerebral cavernousmalformations. Neurosurgery 2000, 46:1272–127754.Zimmerman RS, Spetzler RF, Lee KS, ZabramskiJM, Hargraves RW: Cavernous malformations of thebrain stem. J Neurosurg 1991, 75:32–39
Wallenberg syndrome, Millard-Gubler syndrome, Weber syndrome, Benedikt syndrome or Parinaud syndrome. Cerebellar hemorrhages in cerebral peduncles or on cerebellar can result in ataxia or nistagmus, but also cerebellar mutism was described. Cerebellar hemorrhage can also result in IV’th ventricle obstruction and hydrocephalus.
May 02, 2018 · D. Program Evaluation ͟The organization has provided a description of the framework for how each program will be evaluated. The framework should include all the elements below: ͟The evaluation methods are cost-effective for the organization ͟Quantitative and qualitative data is being collected (at Basics tier, data collection must have begun)
Silat is a combative art of self-defense and survival rooted from Matay archipelago. It was traced at thé early of Langkasuka Kingdom (2nd century CE) till thé reign of Melaka (Malaysia) Sultanate era (13th century). Silat has now evolved to become part of social culture and tradition with thé appearance of a fine physical and spiritual .
On an exceptional basis, Member States may request UNESCO to provide thé candidates with access to thé platform so they can complète thé form by themselves. Thèse requests must be addressed to esd rize unesco. or by 15 A ril 2021 UNESCO will provide thé nomineewith accessto thé platform via their émail address.
̶The leading indicator of employee engagement is based on the quality of the relationship between employee and supervisor Empower your managers! ̶Help them understand the impact on the organization ̶Share important changes, plan options, tasks, and deadlines ̶Provide key messages and talking points ̶Prepare them to answer employee questions
Dr. Sunita Bharatwal** Dr. Pawan Garga*** Abstract Customer satisfaction is derived from thè functionalities and values, a product or Service can provide. The current study aims to segregate thè dimensions of ordine Service quality and gather insights on its impact on web shopping. The trends of purchases have
Chính Văn.- Còn đức Thế tôn thì tuệ giác cực kỳ trong sạch 8: hiện hành bất nhị 9, đạt đến vô tướng 10, đứng vào chỗ đứng của các đức Thế tôn 11, thể hiện tính bình đẳng của các Ngài, đến chỗ không còn chướng ngại 12, giáo pháp không thể khuynh đảo, tâm thức không bị cản trở, cái được
Le genou de Lucy. Odile Jacob. 1999. Coppens Y. Pré-textes. L’homme préhistorique en morceaux. Eds Odile Jacob. 2011. Costentin J., Delaveau P. Café, thé, chocolat, les bons effets sur le cerveau et pour le corps. Editions Odile Jacob. 2010. Crawford M., Marsh D. The driving force : food in human evolution and the future.
Le genou de Lucy. Odile Jacob. 1999. Coppens Y. Pré-textes. L’homme préhistorique en morceaux. Eds Odile Jacob. 2011. Costentin J., Delaveau P. Café, thé, chocolat, les bons effets sur le cerveau et pour le corps. Editions Odile Jacob. 2010. 3 Crawford M., Marsh D. The driving force : food in human evolution and the future.
