AUTHOR(S): Chin, Lawrence S., M.D.; Raffel, Corey, M.D., Ph.D.; GonzalezGomez, Ignacio, M.D.; Giannotta, Steven L., M.D.; McComb, J. Gordon, M.D. Divisions of Neurological Surgery (LSC, CR, SLG, JGM) and Neuropathology (IG-G), Childrens Hospital of Los Angeles, and the Department of Neurological Surgery (LSC, CR, SLG, JGM), University of Southern California School of Medicine, Los Angeles, California Neurosurgery 31; 863-869, 1992 ABSTRACT: IN A REVIEW of our series of patients with arteriovenous malformations (AVMs), a group with atypical angiographic and histopathological characteristics was discovered. Unlike the typical AVM, these lesions contained normal cerebral tissue between the abnormal vessels. We call these lesions diffuse AVMs, and think that this AVM represents one end of the AVM spectrum from a tight nidus to a diffuse lesion. The mean age of these patients was 18.1 years. Eight patients presented with an intracerebral hemorrhage, two with seizures, one with headache without hemorrhage, and one with ischemic symptoms compatible with vascular steal. Cerebral angiography revealed three AVMs to be 2 to 4 cm in diameter, four were 4 to 6 cm in diameter, and five were >6 cm in diameter. Characteristic angiographic features included multiple small arterial feeders, small ectatic vessels in the malformation itself, multiple small draining veins, and a diffuse, puddling appearance of the contrast dye. Despite 16 operations in 11 patients, complete resection of the AVM was accomplished in only 8. The four patients with residual disease have received radiation therapy. Histopathology of the surgical specimens found AVM vessels interspersed among normal appearing neurons and white matter. Leptomeningeal angiodysplasia was noted when the cerebral cortex was involved. Gliosis was noted in some cases. Diffuse AVMs represent a difficult surgical challenge and recognition of the lesion aids in surgical planning. KEY WORDS: Angiography; Arteriovenous malformation; Central nervous system; Headache; Intracerebral hemorrhage; Seizures; Vascular abnormality The typical arteriovenous malformation (AVM) is a tangle of abnormal arteries and veins without an intervening capillary bed. Furthermore, parenchyma found among the abnormal vasculature is usually reported as absent or highly gliotic and nonfunctional (1,14) . The AVM that appears diffuse on angiography has been studied far less (26). In fact, no series in the neurosurgical literature could be found that addressed this lesion in a comprehensive manner. This subtype of AVM, representing the diffuse end of the spectrum of AVMs, has a distinct angiographic appearance and implies the existence of neural tissue within the malformation. In a review of our series of AVMs, we have encountered 12 examples of diffuse AVMs. The cases are described for their characteristic radiological and pathological findings as well as the treatment dilemmas caused by their diffuse nature. PATIENTS AND METHODS During the period from 1978 to 1990, all AVMs treated at the Childrens Hospital of Los Angeles (30 patients) and from the personal series of adult AVMs of one of the authors (SLG) (150 patients) were reviewed radiologically and histopathologically. Twelve examples of diffuse AVMs were found. Hospital records, angiograms, magnetic resonance imaging (MRI) scans and surgical specimens from these patients were studied. The histopathology of the typical AVMs resected were examined and compared with those AVMs subsequently classified as diffuse AVMs. Size of the AVM was determined by measuring the maximum diameter in a lateral projection with correction for magnification error. Based on size, a grade was assigned using the system of Luessenhop and Rosa (13): Grade I, <2 cm; Grade II, 2-4 cm; Grade III, 4-6 cm; Grade IV, >6 cm (13). A grade was also assigned according to the Spetzler classification which takes into account the size of the lesion, its relationship to eloquent areas of the brain, and its venous drainage patterns (21). A cerebral angiogram was obtained postoperatively in all surgical cases. Neurological outcome was considered excellent if the patient was neurologically normal, good if improvement in an existing deficit occurred but some deficit remained, unchanged if an existing deficit persisted, and poor if the neurological status changed either by appearance of a new deficit or worsening of a preexisting deficit. RESULTS The 12 examples of diffuse AVMs represented 7% of the total number of patients with AVMs, and the 11 pediatric patients comprised 27% of the AVMs in this age group. Table 1 lists the pertinent clinical information. The mean age was 18.1 years (range, 937 yr) with a 1:1 sex ratio. Eight patients had hemorrhage, two had seizures, one had episodes of transient hemiparesis and hemisensory loss compatible with steal phenomenon, and one had headaches alone. No patient had a history consistent with previous hemorrhage. The two most common neurological findings were hemiparesis (3 patients) or altered mental status (3 patients). Other neurological findings were coma (2 patients) and an expressive aphasia (1 patient). Five patients were neurologically normal. By the Luessenhop scale, 3 AVMs were Grade II (24 cm), 4 were Grade III (4-6 cm), and 5 were Grade IV (>6cm). Using the Spetzler classification, there Redistribution of this article permitted only in accordance with the publisher’s copyright provisions. Neurosurgery 1992-98 November 1992, Volume 31, Number 5 863 Diffuse Arteriovenous Malformations: A Clinical, Radiological, and Pathological Description Clinical Study DISCUSSION The classification of vascular malformations in the central nervous system into AVMs, cavernous angiomas, venous malformations, and capillary telangiectasias is well established (15,26). This categorization allows for a uniform grouping anatomically, pathologically, angiographically, and clinically. The category of AVM, however, represents a spectrum of lesions ranging from a small compact nidus of abnormal vessels to the diffuse pattern we describe here. Recognition of the angiographic pattern of a diffuse AVM is important in subsequent surgical planning. Clinical features In this series, diffuse AVMs were seen primarily in the older pediatric patient (mean age, 18.1 yr) and appears distinct from vein of Galen malformations and other giant AVMs of infancy, in that patients with diffuse AVM lack symptoms of cardiac failure and do not develop hydrocephalus (11,12). This age distribution may reflect a population bias caused by the inclusion of patients from a large pediatric center. The incidence of patients presenting with intracerebral hemorrhage in our small series (8 of 12) was less than the reported 75 to 85% in childhood series of AVMs, but more than the 50% incidence reported for adults (5-7,9,14,17,19,20,24). Imaging features Diffuse AVMs appear on cerebral angiograms as a large collection of tortuous vessels with multiple arterial feeders and multiple draining veins. Deep venous drainage is common. An identifiable compact nidus is not seen and an entire lobe of the brain may be involved. Deep gray nuclei may be involved in some cases. Yasargil (26) has reported a similar angiographic appearance of diffuse AVMs. In addition, we have observed a scattered, puddling appearance of contrast dye, which persisted into the late arterial and early venous phase, perhaps signifying an element of stasis or low flow within the malformation. The presence of intervening neural tissue in the malformation can only be inferred from the diffuse appearance of the angiograms. Three patients in this series underwent MRI scans. The MRI scans detected the presence of acute hemorrhage; evidence of old hemorrhage was not seen. In addition, the MRI scans were not helpful in identifying the nature of the neural tissue between the abnormal vessels of the malformation. Histological appearance On histological examination, the vessels of diffuse AVMs and compact AVMs have similar features. A striking difference is seen in the amount of intervening neural tissue, which is either absent or highly gliotic in the compact AVMs. In all of our 11 patients with surgical specimens, the diffuse AVM was noted to contain normal neurons with varying amount of gliosis. The implication is that the brain interspersed between the abnormal vessels is functional. In this respect, these AVMs are similar to venous malformations and capillary telangiectasias which also have normal brain between the vessels of the anomaly (15,26). Embryological considerations The nature of the abnormal embryogenesis of AVMs is unresolved. Two main theories have been promulgated. One assumes failure of capillary bed formation and therefore development of abnormal artery to vein connections in the fetal brain (3,8,10,19, 24) . The second theory suggests that AVMs result from a primary abnormality in the proliferation and metamorphosis of capillaries. The failure of subsequent normal development or remodeling of the capillary plexus results in the final morphology of the malformation (26). The second theory appears to be more compatible with the AVMs we describe. The development of an Redistribution of this article permitted only in accordance with the publisher’s copyright provisions. were 3 Grade II, 3 Grade III, 4 Grade IV, and 2 Grade V. On angiography, the AVMs were large, wedgeshaped, and often appeared to occupy the entire lobe (Figs. 1 and 2). Multiple small arterial feeders and a diffuse, puddling appearance of the contrast agent were seen in all cases. Multiple draining veins were noted in every case, and in 10 of 12 cases, venous drainage was to the deep system. In the 3 patients in whom MRI scans were obtained, the nature of the parenchyma between abnormal vessels was not evident. Histopathological examination of the resected diffuse AVM specimens showed the presence of abnormal arteries and veins typical of an AVM in all cases as well as normal appearing neurons and, in some cases, mild gliosis (Fig. 3A). By contrast, neural tissue, when present, between the abnormal blood vessels of the typical AVM was restricted to thin gliotic bands without identifiable neurons (Fig. 3B). When a diffuse malformation came near the cortical surface, focal leptomeningeal angiodysplasia, consisting of an increased number of leptomeningeal vessels with abnormally thickened walls, was noted (Fig. 3C). Eleven patients underwent craniotomy, and one patient was deemed inoperable and received conventional external beam radiation therapy (30 Gy). Five patients with residual AVM underwent a second craniotomy, and in three the remaining AVM was removed completely. Of the three patients with residual AVM, two underwent stereotactic radiosurgery and one has received no further therapy. The clinical outcome was excellent for eight patients. In the remaining four patients there were two good outcomes, one unchanged, and one poor. The patient with the poor result was left with an expressive aphasia and an increased hemiparesis. There was no surgical mortality or evidence of normal perfusion pressure breakthrough (23). No definitive correlation can be made between preoperative grading and outcome because of the small number of patients, but the two patients with the worst clinical outcomes were Spetzler Grades IV and V. Treatment Diffuse AVMs are difficult to treat effectively as they are both large and complex. This is reflected in the high scores given to the patients in our series using the Spetzler scale (21). The absence of a gliotic plane around a well defined nidus makes total surgical removal more of a challenge. In addition, the presence of normal brain within the lesion means that surgical excision or radiation therapy will result in the sacrifice of normal parenchyma. This precludes surgical treatment when these lesions are located exclusively in cortex with critical function. Anterior frontal, anterior or non-dominant temporal, or parieto-occipital lesions are amenable to surgery, which provides the only opportunity for immediate cure. The traditional principles of AVM resection must be modified (13,14,26). An en bloc approach, such as a lobectomy, may be required for complete removal of all abnormal vessels. The attempt to remove all of the malformation must obviously be weighed against the danger of producing an unacceptable neurological deficit. If there is extension of abnormal vessels into critical areas of the brain such as the thalamus, stereotactic radiosurgery may be useful in obliterating remaining malformation. Our surgical results with incomplete removal of the AVM in 6 of 11 patients with the first attempt, and in 2 of 5 after the second, demonstrate the difficulty in determining the extent of resection intraoperatively. Because of the low rate of flow through the AVM, the surgeon can cut through the lesion without noticing the small, abnormal vessels. The difficulty is increased by the lack of a gliotic plane around the lesion. Intraoperative angiography was not available at the time of these operations. Although small residual portions of the AVM can be missed with intraoperative angiography, it will be used in future cases. Postoperative angiography is essential to verify complete removal. There were four patients with residual AVMs. Two underwent stereotactic radiosurgery. This modality has had some success in obliterating small AVMs (18) . Colombo et al. (2) achieved obliteration at 2 years in 90% of AVMs <15 mm and 80% of AVMs between 15 and 25 mm. Follow-up on these two patients has not been long enough to know whether the treatment has been effective. One patient had a poor result after the initial surgical attempt at removal, and further treatment of his residual AVM has not been undertaken. One patient with a >6 cm AVM involving the left basal ganglia and thalamus never underwent surgical intervention. This lesion was too large for stereotactic radiosurgery and the multiple small feeders made embolization impossible. She underwent conventional radiation therapy with 30 Gy with resolution of the steal phenomenon. The status of her AVM is not known, because repeat angiography has been refused. Conventional radiation therapy has been found to be of modest efficacy in the treatment of AVMs (18). Staged embolization with operative excision of large AVMs has been advocated to lessen the risk of normal perfusion pressure breakthrough (22). Embolization was only used in two patients in our series, yet we did not encounter this complication in any of our patients. The low flow nature of these malformations, despite their large size, is likely the reason that normal perfusion pressure breakthrough was not noted. Diffuse AVMs are large vascular malformations with a tendency to hemorrhage in late childhood and early adulthood. The unique angiographic features can be recognized preoperatively and aid in surgical planning. The presence of normal neural tissue interspersed among the vessels of the malformation requires caution during resection. Nonetheless, an en bloc resection of brain may be necessary to completely remove the malformation. Received, March 25, 1992. Accepted, May 11, 1992. Reprint requests: Corey Raffel, M.D., Ph.D., 1300 North Vermont Avenue, Suite 906, Los Angeles, CA 90027. REFERENCES: (1-26) 1. 2. 3. 4. 5. 6. 7. Anderson FM, Korbin MA: Arteriovenous anomalies of the brain. 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Redistribution of this article permitted only in accordance with the publisher’s copyright provisions. abnormal capillary bed into a large plexus of vessels which grows with the developing brain and does not hemorrhage or cause ischemic damage to intervening brain may result in a diffuse AVM. Later on, with repeated hemorrhages, recruitment of new vessels, expansion of the nidus, and gliotic changes in the neural tissue, the diffuse type AVM may transform, in some cases, into a more typical, compact lesion. The absence of chronic hemorrhage as noted on the MRI scans is indirect support for this idea. In addition, the dynamic nature of AVMs with respect to change in size and appearance is well documented (4, 16,25) . 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. Garretsen HD: Intracranial arteriovenous malformations, in Wilkins RH, Rengachary SS (eds): Neurosurgery. New York, McGrawHill, 1985, pp 1448-1458. 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Spetzler RF, Wilson CB, Weinstein P, Mehdorn N, Townsend J, Telles D: Normal perfusion pressure breakthrough theory. Clin Neurosurg 25:651-672, 1978. Stein BM, Wolpert SM: Arteriovenous malformations of the brain. Arch Neurol 37:15, 1980. Waltime O: The change in size of intracranial 26. arteriovenous malformations. J Neurol Sci 19:21-27, 1973. Yasargil MG: Microneurosurgery. Stuttgart, George Thiem Verlag, 1987, vol IIIA, pp 23160. COMMENTS Chin et al. have reported 12 interesting cases of socalled diffuse arteriovenous malformations (AVMs). The authors suggest that these lesions are a subtype of AVMs that reflect the diffuse end of the spectrum of AVM morphology. The critical characteristic for differentiating these lesions from typical AVMs is significant amounts of presumably normal brain parenchyma within the diffuse AVM nidus. The excess parenchyma makes surgical treatment difficult when these AVMs are located in eloquent areas of the brain. Nonetheless, the authors report favorable results after surgery in most cases (with additional radiosurgery in a few cases). The cases span a 12-year period during which adjuvant treatments such as stereotactic radiosurgery and advanced embolization techniques become an important part of the treatment for AVMs. We have also seen many cases of large diffuse AVMs, most of which have not been localized sufficiently within the anterior frontal or temporal regions to permit complete excision or lobectomy. Several of these AVMs extended into the thalamus and other critical subcortical areas. Our recent attempts to treat these deep lesions by intraoperative glue embolization appear to be promising. We combined this technique with surgical excision of accessible portions of the AVM and, when necessary, with stereotactic radiosurgery of the residual portions. Chin et al. used embolization to treat two of their patients but did not discuss the efficacy of this preoperative treatment. We agree that these large, diffuse lesions represent an extremely challenging type of AVM to treat safely. Chin et al. have made a valuable contribution by demonstrating the presence of normal brain tissue within the diffuse nidus. Some of their cases predate radiosurgery and advances in endovascular techniques, which now offer additional means of treating these AVMs. Nonetheless, it is important to recognize these lesions as one end of the spectrum of AVM morphology and that their treatment carries a high risk to interspersed normal brain. With careful use of combined therapies, however, most of these AVMs can be treated effectively. John A. Anson Robert F. Spetzler Phoenix, Arizona Chin et al. have very carefully described what I think is a very important neurovascular entity that has substantial importance to the patient and must be recognized preoperatively. Diffuse AVMs with intervening functional brain tissue carry a substantial Redistribution of this article permitted only in accordance with the publisher’s copyright provisions. 8. risk of incomplete resection, as the authors have demonstrated, as well as neurological injury with complete resection. We have clearly seen evidence on magnetic resonance imaging scan of diffuse malformations with definite intervening gray and white matter among the vascular flow voids. At surgery, one can be deceived by an apparent gliotic tissue plane apparently marginating the malformation when, in fact, one is simply cutting across a small tuft. In addition to the obvious hazard of resecting an eloquently located malformation of this type, I am concerned about the impact of stereotactically delivered high dose radiotherapy because of the risk of symptomatic brain necrosis in the intervening brain tissue. We have seen this entity in a number of middle-age and older adults, and I suspect the skew in the present series toward younger people simply reflects the inclusion of a population based at the Childrens Hospital. Based on the authors' experience, for a grading scale to be truly predictive, the actual physical characteristics of the malformation (diffuse or compact) must be taken into consideration. Redistribution of this article permitted only in accordance with the publisher’s copyright provisions. H. Hunt Batjer Dallas, Texas Redistribution of this article permitted only in accordance with the publisher’s copyright provisions. Figure 1. Right internal carotid angiogram in the anteroposterior projection showing the typical features of a juvenile diffuse AVM. A, arterial phase angiogram revealing multiple small feeding vessels arising from the anterior and middle cerebral arteries. B, a slightly later film demonstrates the small caliber of the vessels in the ill-defined nidus. Redistribution of this article permitted only in accordance with the publisher’s copyright provisions. Figure 2. Right internal carotid angiogram in the lateral projection demonstrating the typical features of a juvenile diffuse AVM. A, arterial phase angiogram demonstrating the diffuse, ill-defined nidus made up of small vessels. B, late venous phase angiogram showing the puddling appearance with persistence of the contrast agent in the vessels of the malformation. Redistribution of this article permitted only in accordance with the publisher’s copyright provisions. Figure 3. Photomicrographs demonstrating the typical features of juvenile diffuse AVMs. A, juvenile diffuse AVM involving both cerebral cortex and white matter. Some blood vessels have an internal elastic lamina (arrow) and are easily identified as arteries; others are clearly veins. The majority of vessels, however, are difficult to classify (VerhoeffVan Gieson stain, ×200). B, abnormal, dilated vessels Table 1. Clinical Data for Diffuse AVMs Redistribution of this article permitted only in accordance with the publisher’s copyright provisions.