Late complications of radiosurgery for cerebral arteriovenous malformations: report of 5 cases of chronic encapsulated intracerebral hematomas and review of the literature

Background Chronic encapsulated intracerebral hematomas (CEIHs) are a rare, late complication of radiosurgery for intracranial AVM. We present 5 cases treated mostly by surgical excision and review the literature. Methods Patients (age 39, 42, 36, 31, 62) presented with headache, paresthesia, hemiparesis or were asymptomatic. CEIHs presented 10 to 13 years (median 12 years) post radiosurgery. Three patients had demonstrated early radiation induced changes post radiosurgery. Angiographic cure, assessed with DSA, was present in all cases except 1 case with a small nidus remnant. MRI demonstrated mixed lesions with a solid enhancing part, organized hematoma and extensive surrounding edema while three cases had also a cystic component. Results Excision of the CEIHs with complete or partial removal of the capsule was performed in 4 patients and resulted in marked clinical improvement. One patient was managed conservatively with administration of steroids as surgery was judged excessively hazardous with eventual stabilization of his symptoms. Conclusions CEIHs are rare, late complications of radiosurgery for cranial AVM. They may be asymptomatic or provoke symptoms and may be preceded by early radiation induced changes. Complete removal of CEIHS is an effective treatment. Because of the long latency period of CEIHs, patients who had radiosurgery for brain AVMs should be followed by MRI at least 10 years even after complete obliteration.

We report 5 cases of CEIH that developed in patients with bAVMs that had been completely obliterated using SRS and review the literature.

Materials and methods
The Neurointerventional Department of the University of Nancy, Nancy, France, is a tertiary center serving a region of 2,35 million inhabitants. We reviewed our medical records for the period 1997 to 2014 during which 288 patients were treated with radiosurgery for a brain arteriovenous malformation. We obtained the presentation, diagnosis, management and clinical outcomes of 5 cases of interest. Because of the retrospective nature of the study, permission from the ethics committee of our institution was not necessary. This research complies with the STROBE (Strengthening the Reporting of Observational studies in Epidemiology) reporting guidelines. We also performed a comprehensive literature search using Pubmed. The following key words were queried singly and in combination: arteriovenous malformation, brain, hematoma, radiosurgery. Our search resulted in case reports and cases series describing CEIH post bAVM SRS. In all cases that could be extracted (including ours and the cases in the referenced articles), we collected the clinical presentations, imaging findings, management and outcome.

Illustrative cases
Three of the 5 patients were males. The mean patient age was 30,8 years (range 27 to 49 years). The presenting symptom was seizures in 3 cases and hemorrhage in 2 cases. AVMs were located in the temporal lobe in 2 cases, and the parietal, frontal and occipital lobes in the other cases. All lesions were partially embolized prior to radiosurgery. The marginal dose delivered was 18 Grays for all lesions. The mean irradiated nidus volume was 5,2 ml (range 3,8 to 9 ml). Four of five AVMs were angiographically obliterated post radiosurgery. Three cases demonstrated RICs following radiosurgery. The mean time of CEIH presentation was 10,2 years post radiosurgery (range 6 to 13 years). MRI studies showed hemorrhagic lesions with extensive peri-lesional edema (Fig. 1). A cyst coexisted with the hemorrhagic lesion in 3 cases (Fig. 2). Three cases were immediately treated with surgical excision of the hemorrhagic lesion and the cystic component. Two cases were treated conservatively with steroid administration. One of these cases showed interval growth and symptom worsening after 2 years and was eventually treated surgically while the other case remained clinically stable during a follow-up period of 8 years (Fig. 3). All surgically treated cases demonstrated typical histological features of CEIH and clinical improvement.

Literature search
We found 32 cases of CEIH in case reports and case series. Reports with insufficient or no data were excluded. In total, 37 cases including our own 5 cases were analyzed (Table 1).
Data on the therapeutic management were available in 35 patients. Complete excision was performed in 10 cases and led to clinical and/or radiological improvement in 9 patients, while 1 remained stable. Three cases were treated with partial excision with good results. Four patients had only the cystic component treated (2 patients with Omaya reservoir placement and 2 patients with evacuation). However, this approach failed to     Radiological and/or Clinical Improvement provide clinical improvement in 3 patients who eventually underwent complete excision with good results. Follow-up or medical management with steroids was attempted in 18 patients of whom 16 eventually underwent excision and 1 partial excision because of lesion enlargement or non-improving symptoms. In this group, improvement was reported in 9 patient, 1 patient with partial excision experienced worsening while 7 patients were lost to follow-up. Surgery was judged hazardous in one patient (patient 5 in the present series) who remained clinically stable at 8 years follow-up.

Discussion
Chronic encapsulated intracerebral hematomas are a very rare complication of radiosurgery for cerebral AVM. The incidence in our cohort of treated patients was 1,8% of patients with brain AVM treated with SRS over a period of 17 years. Other series attest to the rarity of this complication with reported incidences ranging from 0,6 to 4% [1,16,24,25]. However, the long latency period of CEIHs and the cessation of imaging controls once nidus obliteration has been documented may have led to the underestimation of the true prevalence [26]. Longer periods of imaging follow-up, at least years post radiosurgery have been suggested [19].
Histologically CEIHs are made of a thickened hematoma capsule with abundant microvasculature that can easily bleed when removed surgically. The hematoma itself is serous and is usually easily aspirated. The gross appearance is similar to chronic subdural hematoma. CEIHs may develop near vascular lesions such as AVMs, cavernous angiomas and venous angiomas. It is thought that CEIHs develop secondary to hemorrhagic episodes of the initial angiomatous lesion with its eventual "self-destruction" or thrombosis [4,16,27,28]. In the case of post radiosurgery obliterated AVMs, it is thought that radiation-induced inflammation triggers neoangiogenesis of fragile new vessels, breakdown of the bloodbrain barrier, fluid exudation in the nearby brain, edema and potential cyst formation. Dense vascularization has been found in the capsule of CEIHs and it is thought that bleeding of these fragile vessels results in expansion of the capsule and further bleeding, a mechanism similar to chronic subdural hematoma [23,[29][30][31]. Neovascularization and hematoma expansion appear to be mediated by VEGF (Vascular Permeability Factor), a potent vascular endothelial cell mitogen that promotes neovascularization and vascular permeability [22] associated also to chronic subdural hematoma pathophysiology. Further studies are needed to elucidate the mechanisms of CEIHs post AVM radiosurgery.
On MR imaging, a common finding in all cases of CEIHs was extensive perilesional edema. Most cases demonstrated as low intensity or heterogeneous lesions on T2 weighted imaging with or without a hypodense rim. On contrast enhanced T1 weighted images there existed usually nodular or multinodular enhancement (Table 1). CEIHs were associated with cyst in 62,1% of cases pointing to a possible common pathophysiologic mechanism [3]. The latency time from radiosurgery to CEIHs diagnosis was 7,7 years sd 3,7 years. Symptoms, the most common being from headache (44,8%), hemiparesis (41,3%), nausea/vomiting (13,7%) were mostly related to the mass effect of the gradually growing CEIH and the surrounding edema.
Several risk factors have been explored for the development of CEIHs including age, sex, basal ganglia AVM location, irradiated nidus volume, the marginal or total dose, early RICs, repeat radiosurgery, nidus obliteration, pre-radiosurgery embolization, pre-radiosurgery surgery and prior hemorrhage with inconsistent results [16,25,26,28,32]. In the present review, the distributions of age, sex, location, marginal dose, nidus obliteration and pre-radiosurgery embolization did not differ from distributions seen in cohorts of AVMs treated by radiosurgery. However, the incidence of radiation induced changes in the years post radiosurgery was unusually high (32, 4%). There was also a high percentage (18,9%) of cases which had received repeat radiosurgery. Further studies are needed to ascertain the risk factors and mechanisms of CEIHs that develop post SRS for AVM [14].
CEIHs often caused progressive neurological deficits due to mass effect. The most efficient treatment was complete excision that led to clinical and/or radiological improvement in cases. Partial treatment was less efficient and had to be complemented by complete excision in cases. Conservative management consisting of follow-up or steroid administration was unsuccessful in most cases and had to be complemented by total excision of the hematoma and the capsule to achieve good clinical outcome.
This study is susceptible to a number of biases inherent to any retrospective study and review like the small number of cases, selection bias and publication bias. The time CEIHs were detected was mostly based on the timing of symptom development and asymptomatic CEIHs may have been underreported. Larger studies are needed to further elucidate the pathophysiology, incidence and risk factors related to the development of CEIHs post cerebral AVM radiosurgery.

Conclusion
CEIHs are a rare late complication that develop after SRS to treat cerebral AVMs. A potential risk factor is the appearance of radiation induced changes post SRS. CEHIs become usually symptomatic because of their mass effect and extensive surrounding edema. To manage these symptoms, CEIHs should ideally be evacuated with complete capsule removal. Partial capsule removal in the case of lesions in eloquent regions may be an alternative treatment.