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  • 1. Intracerebral hemorrhage: non-hypertensive causes. C S Kase Stroke. 1986;17:590-595 doi: 10.1161/01.STR.17.4.590 Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1986 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. Online ISSN: 1524-4628The online version of this article, along with updated information and services, is located on the World Wide Web at: http://stroke.ahajournals.org/content/17/4/590.citationPermissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published inStroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.Once the online version of the published article for which permission is being requested is located, click RequestPermissions in the middle column of the Web page under Services. Further information about this process isavailable in the Permissions and Rights Question and Answer document.Reprints: Information about reprints can be found online at:http://www.lww.com/reprintsSubscriptions: Information about subscribing to Stroke is online at:http://stroke.ahajournals.org//subscriptions/ Downloaded from http://stroke.ahajournals.org/ by guest on October 15, 2012
  • 2. 590 Progress Reviews Intracerebral Hemorrhage: Non-Hypertensive Causes CARLOS S. KASE, M.D.SPONTANEOUS, non-traumatic intracerebral hemor- small and medium-size arteries of the cerebral hemi-rhage (ICH) in the adult is most commonly secondary spheres. The arteries affected are preferentially locatedto hypertensive cerebrovascular disease. In 70-90% of in the superficial layers of the cerebral cortex and thecases of spontaneous ICH, arterial hypertension is the leptomeninges,6-7 cerebral amyloid angiopathy (CAA)presumed cause.1 These hypertensive hemorrhages being virtually absent in the deep grey nuclei, whereshow a predilection for certain anatomic locations: the ICH of hypertensive origin predominates. CAA is abasal ganglia (the putamen in particular), the subcorti- condition restricted to the cerebral vasculature, since itcal white matter, and the thalamus account for 35%, is not associated with systemic vascular amyloidosis,825%, and 20% of ICHs, respectively, whereas the and it is almost always of sporadic occurrence, al-posterior fossa locations, the cerebellum and pons, are though familial incidence has been documented in Ice-responsible for only 10% and 5% of the cases.2 Irre- land9 and in the Netherlands.10 In these the condition isspective of their anatomic locations, the common inherited as an autosomal dominant trait, and leads topathogenesis in these hemorrhages involves the hyper- ICH early in life, especially in the Icelandic families,tension-induced degeneration of the media of small in which the majority of the ICHs occurred in the third(50-200 micra) arteries called "lypo-hyalinosis,"3 and/ and fourth decades. In a group of these patients it hasor the formation of "microaneurysms", both of which beenrecentlyshown that the basic abnormality appearsoccur preferentially in perforating or small sub-cortical to be in the metabolism of an alkaline microproteinarteries, thus resulting in the characteristic anatomic called "y-trace", which is found in abnormally lowdistribution of hypertensive ICH. concentrations in the CSF of these patients, as com- A significant number of cases of ICH are due to pared with controls." An abnormality in the catabo-causes other than hypertension. The frequency of such lism of this microprotein is thought to cause the vascu-cases varies from 25% to 50% among series, and de- lar deposition of amyloid fibrils.pends on the anatomic type of ICH being considered: The common sporadic variety of CAA typically af-non-hypertensive mechanisms may account for as fects elderly individuals. Its incidence in autopsy se-many as 55% of "lobar" ICH cases,43 while pontine ries increases with age, from a mere 8% in the seventhhemorrhage is virtually always (90%) hypertensive, decade, to close to 60% in individuals older than 90.7and the deep ganglionic (putaminal, thalamic) and An association with Alzheimers disease has long beencerebellar varieties occupy an intermediate position recognized, particularly in regards to a high frequency(35%, 25%, and 38% being of non-hypertensive of some of its histopathologic features in brains ofmechanism, respectively). Among the many possible patients with CAA. In at least 50% ofreportedcases ofmechanisms of ICH not primarily related to hyperten- CAA, neuritic plaques have been documented, with asion, there are several that occur with high enough lower frequency of detection of neurofibrillary tan-frequency to warrant separate discussion. These gles. The presence of clinical progressive dementia ofcauses of ICH are related to special types of arterial the Alzheimer type has been reported with differingpathology, to the presence of brain tumors, or to the frequency in various series, affecting from 10% touse of medications, and include: cerebral amyloid an- 30% of the patients.6-12 Pathologically, CAA is charac-giopathy, small vascular malformations, primary or terized by deposits of Congo-red positive material inmetastatic brain tumors, oral anticoagulants, and am- the media and adventitia of cortical and leptomenin-phetamines and a variety of other sympathomimetic geal arteries. These Congo-red stained vessels showdrugs. characteristic bi-refringence under polarized light, and also exhibit fluorescence with thioflavin T staining. Cerebral Amyloid Angiopathy Electron microscopic studies demonstrate the typical This condition is a unique form of angiopathy due to non-ramified 90-110 A diameter amyloid fibrils with-deposits of amyloid in the media and adventitia of in the vessel wall. These lesions often lead to thicken- ing of the vascular wall, with stenosis or obstruction of the lumen,resultingin small foci of necrosis (infarcts), which are rarely if ever symptomatic. The only consis- From the Department of Neurology, Boston University School ofMediciDe, Boston, Massachusetts. tent clinical result of CAA is ICH following rupture of Address correspondence to: Carlos S. Kase, M.D., Department of an affected artery, due to either "weakening" of theNeurology, Boston University School of Medicine, 720 Harrison Ave- wall by the amyloid deposits, or to rupture of a secon-nue, Suite 604, Boston, Massachusetts 02118. dary "microaneurysm" developed at sites of amyloid Received September 10, 1985; revision #1 accepted December 24, deposition.6l21985. Downloaded from http://stroke.ahajournals.org/ by guest on October 15, 2012
  • 3. INTRACEREBRAL HEMORRHAGE: NON-HYPERTENSIVE CAUSES/Kase 591 The ICHs from CAA characteristically occur in su- hematoma. The histologic type of vascular malforma-perficial, subcortical or "lobar" locations, since the tions leading to ICH most frequently corresponds toangiopathy selectively affects arteries of the cortical AVMs or venous angiomas, the cavernous angiomasurface and leptomeninges. Furthermore, these sub- variety being rarely associated with bleeding. AVMscortical ICHs have shown, in some series, a predilec- usually become symptomatic at a relatively early age,tion for the posterior aspects of the cerebral hemi- most commonly in the third and fourth decades, thusspheres,reflectinga generally heavier concentration of representing a potential source of ICH in non-hyper-CAA-affected arteries in the parietal and occipital tensive young populations.l8 A striking female prepon-lobes.613 In some instances, subarachnoid or subdural derance of these small vascular malformations hashemorrhages have coexisted, again reflecting the su- been reported in several series.17l8perficial location of the vascular lesions. An additional Their clinical presentation is that of ICH in anyfeature of ICH related to CAA has been a tendency to location, deep or superficial, without specific clinicalproducerecurrenthemorrhages over periods of months features, other than perhaps a relatively slower courseor years,14 occasionally even leading to simultaneous of development, as compared with the more abrupt andacute intracerebral hematomas in two different brain rapidly evolving course of hypertensive ICH. Thelocations. In a number of published reports a history of hemorrhages produced by these lesions tend to be morehead trauma or, less commonly, a prior neurosurgical often at the level of the cerebral convexity (subcorticalprocedure has preceded the onset of CAA-related ICH. white matter) than in the deep portions of the hemi-This raises the possibility that some of these hemor- sphere, reflecting their usually more superficial loca-rhages may be related to trauma, and the potential for tion, a feature also documented for non-ruptured smallsuch complication should be recognized when a neuro- cerebral vascular malformations incidentally found atsurgical procedure (such as ventricular shunt insertion, autopsy. Due to their small size, the usual absence ofbrain biopsy) is indicated for elderly demented pa- symptoms prior to the onset of ICH, and the difficultytients. Furthermore, the need for meticulous hemosta- in diagnosing them in life, these malformations havesis following surgical evacuation of ICHs in the elderly been called "cryptic" by some authors.16 On occasionscannot be overemphasized. Some authors12 have con- there is a family history of such vascular malforma-sidered ICH from CAA a condition with poor vital tions and ICH," but they occur more commonly on aprognosis, on account of a generally larger size of the sporadic basis. Since their documentation can result inhemorrhages, and their tendency to recur. It is possible successful surgical therapy and prevention of recurrentthat systematic search for this etiology in specimens ICH, angiography should be considered part of thefrom surgically-evacuated intracerebral hematomas routine evaluation of non-hypertensive patients pre-will provide an accurate estimate of the true frequency senting with spontaneous ICH, in particular if the hem-of CAA in cases of spontaneous ICH. Only then will orrhage is located in the subcortical white matter of aits prognosis and tendency to post-operative local re- cerebral hemisphere. In a number of instances, pre-currence be documented. operative angiography has failed to document a vas- In conclusion, CAA is probably an important etiolo- cular malformation that was diagnosed histologicallygic factor for ICH in non-hypertensive elderly individ- following surgical evacuation of an intracerebral he-uals who present with single or recurrent hemorrhages matoma. l 7 " These patients have usually had smallof subcortical "lobar" location. The actual frequency AVMs or venous angiomas. The difficulties in demon-of this disorder is unknown, but is probably quite high strating the latter lesion angiographically probablyin elderly populations." It is expected that increased stem from their small size and lack of multiple tortuousawareness of this condition will lead to more accurate vascular channels, as well as the absence of arterioven-estimates of its frequency in surgical and autopsy ous shunting of blood leading to marked dilatation ofspecimens, and this effort may eventually result in venous structures. In the case of small AVMs, lack ofeffective measures for its treatment and prevention. angiographic demonstration may at times reflect com- pression by an adjacent hematoma, since repeat angio- grams following resorption of the hematoma have oc- Small Vascular Malformations casionally disclosed mem. Spontaneous thrombosis These correspond to previously unsuspected small may be an additional reason for lack of angiographicintracerebral arteriovenous malformations (AVMs), visualization of malformations. Due to the potentiallycavernous angiomas, or venous angiomas, that present negative angiograms in the setting of an acute ICH dueas spontaneous ICH in adult life. Their reported fre- to one of these malformations, some authors have rec-quency in series of ICH has varied between 4 and 8% ommended surgical evacuation of intracerebral hema-of the cases.16 " The diagnosis is usually established tomas in young non-hypertensive patients,17 since theby cerebral angiography or, more commonly, follow- resection of this type of lesion will likely prevent ICHing histologic study of biopsy specimens taken at the recurrence.time of surgical evacuation of the ICH. With the intro-duction of CT scanning, an increasing number of theselesions are being diagnosed by the demonstration of Brain Tumorscalcium deposits in their vicinity or, more commonly, Hemorrhage into a brain tumor is a relatively rare,by the post-contrast opacification of abnormal serpigi- but well documented, cause of non-traumatic, non-nous vascular channels adjacent to an intracerebral hypertensive ICH. In series of brain tumors, ICH oc- Downloaded from http://stroke.ahajournals.org/ by guest on October 15, 2012
  • 4. 592 STROKE VOL 17, No 4, JULY-AUGUST 1986curs in less than 1% of these cases, whereas underlying acute effects of the ICH leading to uncal herniation andtumors in ICH series are found in 2 to 6% of the brainstem compression or, less commonly, to the pro-cases,2021 occasionally in as many as 10% of the gression of the underlying malignant tumor.23cases.22 These are instances of ICH in either a pre-viously unknown cerebral neoplasm or, more com- Oral Anticoagulantsmonly, as a complication of a known brain tumor. As a Warfarin sodium, a widely used oral anticoagulantresult, ICH produces the acute onset of either a new for the prevention of venous and arterial origin embo-focal neurologic deficit, or worsening of pre-existing lism, is associated with bleeding complications in ap-focal deficits, in both instances commonly associated proximately 7-8% of patients.2*-27 Intracranial hem-with deterioration in the level of consciousness. The orrhage accounts for a small fraction of thesebrain tumors likely to present as ICH are largely malig- hemorrhages, amounting to only 0.5-1.5% of allnant, either primary astrocytoma (glioblastoma multi- bleeding events related to warfarin. However, theseforme) or metastatic, most commonly bronchogenic intracranial hemorrhages have a generally dismalcarcinoma, melanoma, choriocarcinoma, or renal-cell prognosis, thus resulting in a significant contributioncarcinoma.2124 Benign brain tumors such as meningio- to the fatal complications of oral anticoagulantmas or oligodendrogliomas have rarely been reported therapy.as presenting with episodes of non-traumatic ICH. The The common intracranial sites of bleeding in orallybleeding potential of malignant tumors is thought to be anticoagulated patients are, in decreasing order of fre-related to their tendency toward spontaneous necrosis quency, the subdural space, brain parenchyma, andand to the richness and neoplastic character of their subarachnoid space. ICH in this setting represents avasculature, as well as the biologic tendency of some condition with some distinct clinical characteristicstumors such as choriocarcinoma to invade the walls of and course, as well as high mortality and serious long-blood vessels. Metastases from this tumor are note- term sequelae in survivors. Oral anticoagulation hasworthy for their tendency to become hemorrhagic in at been estimated to increase between 8-fold28 and 11-least 50% of the cases.24 fold29 the risk of ICH, as compared with non-anti- The sites of ICH relate in some degree to the type of coagulated individuals with similar risk factors forunderlying tumor, since deeply-seated white matter intracranial hemorrhage. A number of possibly con-tumors such as glioblastoma multiforme will produce tributing factors to ICH have been suggested in thisdeep hemispheric hemorrhages, while those resulting patient population: A) Age. Several studies have indi-from metastatic tumors are more often cortico-subcor- cated a low frequency of ICH in patients younger thantical, reflecting the predilection of secondary tumors 50, and an increased risk for ICH as a function offor the superficial portions of the cerebral hemi- increasing age,29 some suggesting age 65 as a point ofspheres. Most commonly, these hemorrhages originate sharp rise in the risk.28 Although other series haveat the margins of the tumor, or between the tumor and failed to show a clear relationship between increasingthe adjacent edematous brain parenchyma.21 Instances age and higher risk of bleeding in anticoagulated pa-in which an underlying tumor is suspected in a patient tients,2* we believe that this form of therapy should bewith ICH include: (a) History of preceding chronic given to patients who are older than 70 years of ageheadache and/or focal neurologic deficit and/or per- only after close scrutiny of its indications and thesonality change for days or weeks prior to the onset of subjects ability to comply with its proper use andICH, or the finding of papilledema on initial presenta- monitoring. B) Hypertension. The contribution of thistion with ICH; (b) The presence of multiple separated factor to warfarin-related ICH has also been controver-foci of ICH occurring simultaneously; (c) An area of sial, some series strongly suggesting a relationship,29"ring-like" hemorrhage with a low-density center in while others have failed to document it.28 As a result,non-contrast CT scan; (d) An ICH that on CT scan there are no defined guidelines for the indications orappears as irregular, mottled high-density, and affect- contraindications for oral anticoagulants in hyperten-ing structures that are rarely involved in hypertensive sives. It is our policy to exclude from chronic warfarinICH, such as the corpus callosum, which on the other therapy patients who continue to have severe and labilehand is frequently affected in glioblastoma multi- hypertension in the face of full compliance with maxi-forme; (e) A disproportionate degree of surrounding mal anti-hypertensive therapy. C) Preceding cerebraledema and mass effect associated with the hematoma; infarction has been considered by some to be important(f) Presence of post-contrast enhancement in the vi- in the pathogenesis of anticoagulant-related ICH.30cinities of the acute high-density ICH. An angiogram However, recent large series29-3I have failed to supportcan be useful in demonstrating a mass lesion with the such an association: in a group of 24 patients with ICHclassical "tumor blush" characteristic of highly vascu- in the course of warfarin therapy,31 only 1 bled into thelar primary or metastatic brain tumors. In many in- area of the brain that had 3 weeks before been affectedstances the diagnosis is only suspected by the finding by an embolic infarct; all others with prior embolicof clinical or radiologic signs of a systemic malignan- infarcts (8 patients) had ICH in a vascular territorycy, or it is established by biopsy of the hematoma different from that involved previously. Although ancavity following its surgical evacuation. The prognosis embolic infarct can acutely become complicated by thein this form of ICH is poor, with short-term (days to formation of a hematoma in the setting of heparin orweeks) mortality in the 90% range, mostly due to the warfarin anticoagulation, this phenomenon is uncom- Downloaded from http://stroke.ahajournals.org/ by guest on October 15, 2012
  • 5. INTRACEREBRAL HEMORRHAGE: NON-HYPERTENSIVE CAVSES/Kase 593mon, and appears to be limited to large size embolic noted in one series,31 and that location was also over-infarcts.32 D) Excessive prolongation of the prothrom- represented in a group of 13 cases gathered from thebin time. With very few exceptions,13 this factor is literature.30-3739 This anatomical feature of warfarin-considered to be a consistent feature in most hemorrha- related hemorrhages has no clear explanation, as it isgic complications in orally anticoagulated patients. also unclear what the actual pathogenesis of these hem-ICH is no exception to this rule: fully 80% of patients orrhages is, in terms of the size and type of the rupturedwith ICH have excessively prolonged prothrombin vessels leading to the hemorrhage. It is possible thattimes (PT) at the onset of hemorrhage. One major these hemorrhages arerelatedto bleeding from vesselsdifficulty in clearly establishing this fact from the lit- different from thoseresponsiblefor hypertensive ICH.erature is the lack of agreement on what the "therapeu- Serial microscopic sections of pathologic specimenstic" PT range is: some authors recommend a prolonga- will be required to clarify these points.tion of the PT to 1 Vi to 2Vi times control,28 "• M while The overall prognosis in these ICHs is poor, withothers use strictly I1/- times control.233 In studies of mortalities in the range of 65% of the cases.293I Thiswarfarin therapy for prevention of venous thromboem- high mortality correlates with generally large size he-bolism, there is evidence that a "low-dose" schedule of matomas, probably reflecting the slow but eventuallywarfarin (enough to prolong the PT to 1VA control) is massive extravasation of blood into the parenchyma asassociated with equal protection, but significantly few- a result of the drug-induced coagulation defect. De-er bleeding complications, than a "conventional" spite the routine use of vitamin K and fresh frozenschedule with PT prolonged to 1 Vi to 2 times control.36 plasma for the rapidreversalof the coagulation defect,Similar comparisons of different schedules of oral anti- neurologic deterioration and fatal outcome is the ex-coagulation are not available for the prevention of arte- pected course in two-thirds of the cases.rial thromboembolism. However, extrapolation fromthe venous thromboembolism data suggest that it is Use of Amphetamines and Otherprudent to recommend adherence to "conservative" Sympathomimetic Drugslevels of warfarin anticoagulation, in the range of 1 Vitimes control, for the prevention of bleeding complica- A number of examples of ICH secondary to the usetions. E) Duration of anticoagulant treatment. This and abuse of amphetamines and related drugs havefactor has not shown a clear association with risk of been documented. The most commonly implicatedICH, since in some series the duration of therapy has preparation has been methamphetamine by the intrave-most often (in 65% of the cases) exceeded 1 year,29 nous route,40 but examples of ICH following its intra-while in others as many as 70% of the events occurred nasal and oral use are also in record. Less frequently,within the first year of treatment.31 In a group of 12 the responsible substances have been amphetaminecases gathered from several reports, the cases were and pseudoephedrine. ICH has generally occurredevenly distributed below and above 1 year of therapy shortly after use of the drug, within minutes to a fewwhen the ICH occurred.3037-39 F) Head trauma does hours after exposure, and the affected individuals havenot appear to play a role in ICH in the setting of oral been in general chronic users, although occasional ex-anticoagulation: only 4 of 24 patients (16%) had a amples have followed alleged first-time use. The ma-preceding history of trauma in a series of anticoagu- jority of the hematomas have been located in the sub-lant-related ICH.31 In all 4 instances the traumatic epi- cortical white matter of the cerebral hemispheres, onlysode was considered mild in nature, and was not asso- occasional ones occurring at the level of the basalciated with loss of consciousness. ganglia.4142 An association with transiently elevated blood pres- The clinical presentation of anticoagulant-related sure has been noted in approximately 50% of the cases,ICH has some distinctive features. A gradual and slow and thisrepresentsa likely etiologic mechanism. How-progression of the focal signs was recorded in 58% of ever, angiographic changes suggestive of vasculitisthe cases in one series, and one-half of these pro- ("arteritis") have also been documented, raising thegressed over exceedingly long periods of time, of 24, possibility of a drug-induced angiopathy as the etiolo-48, and even 72 hours.31 In some instances, this slowly gic factor.43 This view is further supported by the re-progressive course could be correlated with CT-detect- ported disappearance of such angiographic changesed increase in size of the ICH. This feature contrasts following drug discontinuation or the use of steroids.with the usual course of hypertensive ICH, in which This angiopathy, also called "speed arteritis", is char-such a protracted initial course is rarely observed, and acterized angiographically by multiple focal areas ofcoincident enlargement of the hematoma by CT occurs stenosis or constriction of medium-size intracranialexceptionally following admission (observed in only 2 arteries. Pathologic examination of these vessels hasof a personal consecutive series of 100 cases of ICH). shown a necrotizing angiitis similar to periarteritis no-This extended initial course suggests a process of slow dosa characterized by fibrinoid degeneration and ne-bleeding into the parenchyma, different from the usu- crosis of the media and intima of medium-size andally catastrophic course in patients with hypertensive small arteries and arterioles, associated with variableICH. An additional feature in anticoagulant-related degrees of inflammatory leukocytic infiltration of thehemorrhages has been an apparent difference in their vessel walls. At a later, reparative phase of the angiop-topographic distribution, as compared with hyperten- athy, collagen replacement of muscular and elasticsive ICH: a relative predilection for the cerebellum was tissue can follow, at times resulting in the formation of Downloaded from http://stroke.ahajournals.org/ by guest on October 15, 2012
  • 6. 594 STROKE VOL 17, No 4, JULY-AUGUST 1986aneurysmal dilatations of the arterial wall.43 These vas- 6. Okazaki H, Reagan TJ, Campbell RJ: Clinicopathologic studies ofcular changes are considered to be secondary to either primary cerebral amyloid angiopathy. Mayo Clin Proc 54: 22-31, 1979a direct "toxic" effect of the drug or a hypersensitivity 7. Vinters HV, Gilbert JJ: Cerebral amyloid angiopathy: Incidencereaction to the drug or its vehicle. In a few isolated and complications in the aging brain II. The distribution of amyloidinstances, angiography has revealed a coincidental vascular changes. Stroke 14: 924-928, 1983AVM or aneurysm as the source of hemorrhage, which 8. Gilbert JJ, Vinters HV: Cerebral amyloid angiopathy: Incidencehas been parenchymatous or subarachnoid, respective- and complications in the aging brain I. Cerebral hemorrhage. Stroke 14: 915-923, 1983ly.44 45 In these instances, the apparent role of the drug 9. Gudmundsson G, Hallgrimsson J, Jonasson TA, Bjarnason O:has been that of the precipitant rather than the actual Hereditary cerebral haemorrhage with amyloidosis. Brain 95:cause of the hemorrhage. 387^04, 1972 The usual therapy for this variety of ICH has been 10. Wattendorff AR, Bots GTAM, Went LN, Endtz LJ: Familial cere- bral amyloid angiopathy presenting as recurrent cerebral haemor-the use of high-dose steroids, occasionally accom- rhage. J Neurol Sci 55: 121-135, 1982panied by immunosuppressant drugs (cyclophospha- 11. Grugg A, Jensson O, Gudmundsson G, Amason A, Lofberg H,mide). The clinical picture has followed the expected Malm J: Abnormal metabolism of y-trace alkaline microprotein:course of slow resolution of the intracerebral hemato- The basic defect in hereditary cerebral hemorrhage with amyloido- sis. New Engl J Med 311: 1547-1549, 1984ma, and follow-up angiograms have often shown an 12. Kalyan-Raman UP, Kalyan-Raman K: Cerebral amyloid angiop-improvement or disappearance of the signs of vasculi- athy causing intracranial hemorrhage. Ann Neurol 16: 321-329,tis, attesting to its reversible character. 1984 Phenylpropanolamine, a structural analog of am- 13. Tomonaga M: Cerebral amyloid angiopathy in the elderly. J Amerphetamine contained in over-the-counter appetite con- Geriatr Soc 29: 151-157, 1981 14. Finelli PF, Kessimian N, Bernstein PW: Cerebral amyloid angiop-trol and decongestant preparations, has been associat- athy manifesting as recurrent intracerebral hemorrhage. Arched with ICH in previously healthy individuals.46-w The Neurol 41: 330-333, 1984hematomas have occasionally been multiple and si- 15. Drury I, Whisnant JP, Garraway WM: Primary intracerebral hem-multaneous,47 and a "vasculitic" picture like that seen orrhage: Impact of CT on incidence. Neurology 34: 653-657, 1984 16. Crawford JV, Russell DS: Cryptic arteriovenous and venous ham-in amphetamine-related hemorrhages has also been artomas of the brain. J Neurol Neurosurg Psychiat 19: 1-11, 1956documented. **• ** 17. Steiger HJ, Tew JM: Hemorrhage and epilepsy in cryptic cerebro- Illicit drugs have occasionally been associated with vascular malformations. Arch Neurol 41: 722-724, 1984episodes of ICH closely following their use. These 18. Becker DH, Townsend JJ, Kramer RA, Newton TH: Occult cere-include cocaine,49 and the combination Talwin-pyri- brovascular malformations. A series of 18 histologically verified cases with negative angiography. Brain 102: 249—287, 1979benzamine ("Ts and blues").30 These drugs have at 19. Russell DS, Rubinstein LJ: Pathology of Tumors of the Nervoustimes resulted in the production of cerebral infarction System, Fourth edition, Williams and Wilkins Co., Baltimore, ppinstead of ICH, and both lesions are thought to be the 116-145, 1977result of an angiopathy due to the drug or some of its 20. Russell DS: The pathology of spontaneous intracTanial haemor- rhages. Proc Roy Soc Med 47: 689-693, 1954vehicles. 21. Little JR, Dial B, Bellanger G, Carpenter S: Brain hemorrhage In conclusion, this review of non-hypertensive from intracranial tumor. Stroke 10: 283-288, 1979causes of ICH suggests that these various pathological 22. Scott M: Spontaneous intracerebral hematoma caused by cerebralentities account for a significant number of cases of neoplasms. Report of eight verified cases. J Neurosurg 42:ICH. It is possible that theirrelativecontribution to the 338-342, 1975 23. Mandybur TI: Intracranial hemorrhage caused by metastatic tu-total group of ICH cases will even increase in the mors. Neurology 27: 650-655, 1977future, as the frequency of the hypertensive form of 24. Gildersleve N, Koo AH, McDonald CJ: Metastatic tumor present-ICH is likely to continue to decline, reflecting im- ing as intracerebral hemorrhage. Radiology 124: 109-112, 1977proved control of hypertension in the population at 25. Bitoh S, Hasegawa H, Ohtsuki H, Obashi J, Fujiwara M, Sakurai M: Cerebral neoplasms initially presenting with massive intracere-risk. It is hoped that increased awareness, as well as bral hemorrhage. Surg Neurol 22: 57-62, 1984improved diagnostic methods, willresultin the clinical 26. Coon WW, Willis PW: Hemorrhagic complications of anticoagu-diagnosis of these conditions, which are currently for lant therapy. Arch Int Med 133: 386-392, 1974the most part diagnosed only pathologically. This im- 27. Forfar JC: A 7-year analysis of haemorrhage in patients on long-provement in diagnosis is likely to provide a better term anticoagulant treatment. Brit Heart J 42: 128-132, 1979 28. Furlan AJ, Whisnant JP, Elveback LR: The decreasing incidence ofestimate of their true frequency in the ICH population. primary intracerebral hemorrhage: A population study. Ann Neurol 5: 367-373, 1979 References 29. Wintzen AR, de Jonge H, Loeliger EA, Bots GTAM: The risk of1. Mohr JP, Caplan LR, Melski JW, et al: The Harvard Cooperative intracerebral hemorrhage during oral anticoagulant treatment: A Stroke Registry: A prospective registry. Neurology 28: 754-762, population study. Ann Neurol 16: 553-558, 1984 1978 30. Lieberman A, Hass WK, Pinto R, et al: IntracTanial hemorrhage2. Mohr JP, Kase CS, Adams RD: Cerebrovascular Disorders. In: and infarction in anticoagulated patients with prosthetic heart Harrisons Principles of Internal Medicine, 10th edition, RG Pe- valves. Stroke 9: 18-24, 1978 tersdorf et al (Eds), Chapter 356, pp 2028-2060. McGraw-Hill, 31. Kase CS, Robinson RK, Stein RW et al: Anticoagulant-related New York, 1983 intracerebral hemorrhage. Neurology 35: 943-948, 19853. Fisher CM: Pathological observations in hypertensive cerebral 32. Hart RG, Lockwood KI, Hakim AM et al: Immediate anticoagula- hemorrhage. J Neuropath Exper Neurol 30: 536-550, 1971 tion of embolic stroke: Brain hemorrhage and management options.4. Kase CS, Williams JP, Wyatt DA, Mohr JP: Lobar intracerebral Stroke 15: 779-789, 1984 hematomas: Clinical and CT analysis of 22 cases. Neurology 32: 33. Miale JB: Laboratory Medicine: Hematology, 5th ed, chap 17, p. 1146-1150, 1982 959. CV Mosby, St. Louis, 19775. RopperAH, Davis KR: Lobar cerebral hemorrhages: Acute clinical 34. Braunwald E: Heart Disease, 2nd ed, chap 32, p. 1087. WB syndromes in 26 cases. 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Salanova V, Taubner R: Intracerebral haemorrhage and vasculitis cations of addiction to "Ts and blues". Neurology 32: 623-628, secondary to amphetamine use. Postgrad Med J 60:429-430, 1984 1982 Thrombolytic Therapy in Stroke: Possibilities and Hazards GREGORY J. DEL ZOPPO, M.D., HERMANN ZEUMER, M.D.,* AND LAURENCE A. HARKER, M.D.AGENTS WHICH MEDIATE THE dissolution of patients with various thrombolytic agents, and tothrombi are receiving increasingly wide therapeutic weigh the relative risk of intracerebral hemorrhage inapplication. Urokinase or streptokinase have been em- patients treated with fibrinolytic agents for stroke andployed in the treatment of acute thrombosis of coro- for other thrombotic disorders.nary1"23 and selected peripheral arteries,15 23~34 traumat-ic internal carotid artery occlusion,35 as well as of Mechanism of Thrombolysispulmonary embolism36"39 and peripheral deep venous Arterial thrombosis and thrombus extension involvethrombosis.1340"39 to varying degrees the processes of endothelial injury, The demonstration that acute stroke is typically an platelet aggregation and release, and thrombin genera-atherothrombotic or thromboembolic process60"76 pro- tion. Thrombin-mediated fibrinogen cleavage resultsvides a theoretical basis for the use of thrombolytic in fibrin formation which is required for thrombus sta-therapy in the treatment of acute stroke. However, bilization.80 Thrombin-mediated fibrin formation oc-because of the possibility that intracerebral hemor- curs in direct relation to platelet activation by severalrhage may develop during thrombolytic therapy, use of mechanisms. Platelets promote activation of the earlysuch agents in stroke treatment has generally been con- stages of intrinsic coagulation by a process that in-traindicated. Nevertheless, limited recent experience volves a factor XI receptor and high molecular weightindicates that careful infusion of thrombolytic agents kininogen.81 Also, factors V and VHI interact withmay lead to thrombus dissolution and clinical improve- platelet membrane phospholipids to facilitate the acti-ment in selected patients presenting with acute vation of factor X to Xa and the conversion of pro-stroke.77"79 thrombin to thrombin.82 Platelet-bound thrombin- It is the purpose of this discussion to review the modified factor V (factor Va) serves as a high affinitymolecular basis for the thrombolytic state, clinical platelet receptor for factor Xa.83 Consequently, the rateexperience with systemic and local treatment of stroke of thrombin generation is accelerated 103 fold, provid- ing a potent positive feedback mechanism for initiation From The Roon Research Center for Cardiovascular Disease and of thrombin formation on the platelet surface, fibrinThrombosis, Department of Basic and Clinical Research, Scripps Clime network formation in the thrombus, and indirectly,and Research Foundation, 10666 North Torrey Pines Road, La Jolla, fibrinolysis.California U.S.A. 92037, and from the Abteilung: Neurologie/Neurora- Thrombus dissolution is, in large part, mediated bydiologie, Rheinische — Westphalische Technische Hochschule, Aa-chen, Pauwelsstrasse, D5100, Aachen, Federal Republic of Germany.* fibrinolysis localized within the thrombus.84"86 Fibrin This work was supported in part by research grant HL 31950 from the (and fibrinogen) degradation is catalyzed by plasmin,National institutes of Health. the product of plasminogen activation.87 In the consoli- Address correspondence to: Gregory J. Del Zoppo, M.D., Roon dating thrombus plasminogen binds to fibrin and toResearch Center for Cardiovascular Disease and Thrombosis, Depart- platelets, allowing local release of plasmin within thement of Basic and Clinical Research, Scripps Clinic and ResearchFoundation, 10666 North Torrey Pines Road, La Jolla, California thrombus. The circulating plasminogen activators, tis-U.S.A. 92037. sue plasminogen activator (tPA) and single chain uro- Received February 6, 1986; revision #1 accepted May 12, 1986. kinase plasminogen activator (scuPA), catalyze plas- Downloaded from http://stroke.ahajournals.org/ by guest on October 15, 2012