Letter to the Editor. Radiosurgery for cerebral cavernous malformations: a word of caution

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  • 1 University of Virginia School of Medicine, Charlottesville, VA; and
  • 2 Barrow Neurological Institute, St. Joseph’s Hospital, Phoenix, AZ
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TO THE EDITOR: We read with great interest two articles by Nagy et al.13,14 highlighting their use of stereotactic radiosurgery for the treatment of superficial and deep-seated cerebral cavernous malformations (CMs) (Nagy G, Burkitt W, Stokes SS, et al: Contemporary radiosurgery of cerebral cavernous malformations: Part 1. Treatment outcome for critically located hemorrhagic lesions. J Neurosurg [epub ahead of print July 27, 2018. DOI: 10.3171/2017.5.JNS17776]; Nagy G, Stokes SS, Erőss LG, et al: Contemporary radiosurgery of cerebral cavernous malformations: Part 2. Treatment outcome for hemispheric lesions. J Neurosurg [epub ahead of print July 27, 2018. DOI: 10.3171/2018.2.JNS171267]). These articles address the controversial question of whether radiosurgery provides an improvement over the natural history of CCMs and whether this treatment modality can serve as an alternative to surgery for select patients. The future implications of these papers are significant. Therefore, we address each article separately with the hope of facilitating an open dialogue on this important issue.

In the first article on the use of radiosurgery for the treatment of patients with hemispheric lesions,14 the authors first tackled the question of alterations in natural history caused by radiosurgery. In this cohort, they noted that in the subset of patients without a hemorrhagic presentation treated with radiosurgery, the annual rate of bleeding was 0.4% per lesion; the rate was 2.5% in those with a single prior hemorrhage, and for those with multiple bleeds, this rate was 3.85% for the first 2 years after treatment and 1.3% in long-term follow-up. Several retrospective natural history studies have addressed the rate of hemorrhage of CCMs in superficial locations using a similar methodology to that used by Nagy et al. These studies cited a natural history rate of annual hemorrhage ranging between 0.25% and 2.3% per patient per year.5,9 Prospective studies have cited a higher hemorrhage rate, especially for individuals with a history of a hemorrhage. In these studies, incidental lesions had a hemorrhagic rate of 0.6% per year compared to those with a history of hemorrhage (4.5% per year) and those with a history of seizures (0.4% per year).5,9 In sum, the rates of hemorrhage when treated with radiosurgery versus when not treated with radiosurgery do not appear to be significantly different.

A large recent meta-analysis of 1620 patients demonstrated a 5-year risk of hemorrhage of 3.8% in patients with nonbrainstem CCMs who did not present with intracerebral hemorrhage (ICH) or a focal neurological deficit (FND), or roughly a 0.7% per-year risk of hemorrhage.8 Although there are many statistical nuances associated with the calculation of hemorrhage rates, the rate of bleeding after radiosurgery does not appear to be different from what is known to be the natural tendency of these lesions to bleed and for bleeding episodes to cluster. Not only does radiosurgery provide no protection over the natural history of CCMs, but the series noted 8 treatment failures associated with radiosurgery, with a posttreatment hemorrhage complication associated with a permanent deficit of 4.3% and with radiation toxicity in 2% of patients. The combined posttreatment morbidity rate under this paradigm is therefore 6.3%. Compare this with surgery, in which the rate of permanent deficits after the resection of a cortical lesion has been reported to range between 1.3% and 3.2%.2–4,6 Surgery, therefore, provides a definite cure of CCMs with a more favorable morbidity rate in both the short and long term for superficial lesions. Perhaps most alarming is the finding that in this cohort, pediatric patients had the highest rate of treatment failure. The use of radiosurgery in this context would unnecessarily place the population at highest risk for radiation side effects and with the highest life expectancy at the greatest risk. Further along the same line of discussion, radiosurgery has been shown to lead to the formation of CCMs in a delayed fashion.12 The use of radiation to treat patients at risk for formation of additional lesions, such as familial cases of CCM, may lead to a further increase in disease burden in at-risk populations.

A separate but critical issue addressed by Nagy and colleagues is the question of radiosurgery’s efficacy in seizure control. The authors noted a seizure control rate of 78%–87% for patients with a variety of epileptic presentations, with or without hemorrhage, but they did not provide enough detail for readers to parse out the subtleties required to attribute a role for radiosurgery for seizure control. The reported rates for seizure control in this paper are comparable to those in surgical series.

The second article by Nagy et al.13 addressed a cohort of 210 patients with lesions located in the brainstem, basal ganglia, or thalamus treated with radiosurgery. The authors asserted that radiosurgery results in a decrease in the tendency of deep-seated lesions to bleed. The results of this paper warrant an independent discussion. The natural history of untreated CCMs in deep locations has been the topic of several recent publications. Tian et al. recently reported on the outcome of untreated thalamic CCMs,16 noting an annual hemorrhage rate of 9.7% in this population. The highest rate was observed in patients who presented with hemorrhage and neurological deficits (14.1%), and the lowest annual hemorrhage rate was in those in whom the lesion was identified incidentally (1.2%). Therefore, the natural history of annual hemorrhage in thalamic lesions rests between 1.2% and 14.1%. The natural history of untreated brainstem cavernous malformations has been the topic of two recent studies. Li et al. reviewed the Beijing Tiantan Hospital experience in both pediatric patients and all comers.10,11 In the larger study of 331 patients, they noted that the annual risks of hemorrhage in patients with or without FNDs were 15.9% and 12.4%, respectively. The rate of hemorrhage in patients with incidentally identified lesions was 8.7%. In their pediatric cohort, they noted an annual hemorrhage rate of 11.7%, and they observed a significant decline in rate of hemorrhage 2 years after the initial hemorrhage. Based on a recent large meta-analysis, the estimated 5-year risk of hemorrhage in patients with brainstem CCM presenting with ICH or FND was 30.8%, whereas that for brainstem CCMs without ICH or FND was 8.0%. Therefore, the rate of hemorrhage based on this meta-analysis on a per-year basis is between 1.6% and 6.1%. Nagy et al. cited a lifetime annual hemorrhage rate of 2.4% per lesion for patients with a single hemorrhage. The rate appears to stabilize at 1.1% after an initial increase to 4.3% during the first 2 years after radiosurgery, suggesting that the radiation treatment itself may exacerbate the bleeding risk for a short period. Their annual pretreatment hemorrhage rate was 2.8% for lesions with multiple bleeds prior to radiosurgery, with a pretreatment rebleeding rate of 20.7% (although it is not clear over what period of time), a decrease within the first 5 years, and plateau at 11.5%. They noted that the rebleeding rate fell to 7.9% for the first 2 years after radiosurgery, and it declined to 1.3% thereafter. The rates noted are within the range reported in the literature for risk of rebleeding and fit with what is known about the natural history of lesions followed in the long term: some go on to be dormant. Further troubling is the fact that the conclusions of the authors as to the long-term hemorrhage-free rate in this cohort are based on a single patient using Kaplan-Meier analysis.

The common shortcoming of these natural history studies is their preselection at surgical centers where readily accessible lesions are operated on. Nonetheless, these data support the notion that brainstem CCMs have a higher annual hemorrhage rate than their cortical counterparts; the rate of rehemorrhage is higher; there exists a wide range in the risk of hemorrhage by these lesions and factors leading to hemorrhage are ill-defined; the risk of hemorrhage decreases significantly after the initial period of hemorrhage, but this natural history is not well delineated; and the existing natural history data are heavily influenced by surgical centers and their patient selection criteria.15

Nagy et al. stated that their treatment paradigm consisted of an “early intention to treat paradigm” given that repeated hemorrhages resulted in a significant rate of deficit. However, review of the paper shows that the median age at presentation in this cohort was 37 years but that the median age at treatment was 43 years. This significant discrepancy between ages at presentation and treatment begs the question of whether the patients were truly treated early or if they were treated after a cool-down period, when the risk of hemorrhage from these lesions had decreased. The use of radiosurgery as a treatment option was associated with 11 failures: 5 treated with surgery and 6 requiring retreatment with radiosurgery. Posttreatment hemorrhage was associated with morbidity in 7.4% of patients and radiation-related complications in another 7.2%, for a combined morbidity/complication rate of 14.6%. The mortality rate was 1%. These data compare with a 10%–14% permanent morbidity rate (although the transient morbidity rate is higher) and 1% mortality rate observed with surgery for similar lesions.6,7 Furthermore, surgery is associated with a 2% risk of rehemorrhage per patient1 and, for most lesions, results in a cure, whereas in this study radiosurgery was associated with a significantly higher risk of rebleeding than surgery, a comparable risk of complications, and no apparent alteration in the natural history of brainstem cavernous malformations.

In the search for the ideal treatment for patients with CCMs, practitioners must weigh the risks of their intervention against the natural history of the disease. If the treatment offers no improvement over the natural history, or differently stated, if the risks of complications outweigh the natural history of the disease, one must urge caution with the use of the treatment. The two papers by Nagy et al. reignite discussion on the role of radiosurgery for CCMs. Radiosurgery is thought to obliterate arteriovenous malformations through a sclerosing action on arteries and arterioles, inducing endothelial cell loss and stimulation of smooth muscle cells. CCMs lack these arterial elements, and therefore they lack the biological basis of radiosurgery’s action. With long life expectancies, patients with CCMs should be treated with modalities that offer definitive and durable treatment effects on their lesions. Based on the data from the two papers by Nagy et al. and a review of the existing literature, it does not appear that radiosurgery a) significantly alters the natural history of CCMs; b) offers a “cure” rate comparable with that of surgery; or c) offers a morbidity profile that is better than surgical options, definitely for hemispheric lesions, and most likely for deep-seated lesions; but it does seem that radiosurgery d) provides a higher failure rate than surgery in pediatric patients who are at most risk from radiation and have the longest life expectancy and are therefore at highest risk long-term. We urge caution in interpreting the results of these papers that suggest that radiosurgery is an alternate to surgery or even to observation for patients harboring these lesions.

Disclosures

The authors report no conflict of interest.

References

  • 1

    Abla AA, Lekovic GP, Turner JD, de Oliveira JG, Porter R, Spetzler RF: Advances in the treatment and outcome of brainstem cavernous malformation surgery: a single-center case series of 300 surgically treated patients. Neurosurgery 68:403415, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Amin-Hanjani S, Ogilvy CS, Ojemann RG, Crowell RM: Risks of surgical management for cavernous malformations of the nervous system. Neurosurgery 42:12201228, 1998

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Bertalanffy H, Benes L, Miyazawa T, Alberti O, Siegel AM, Sure U: Cerebral cavernomas in the adult. Review of the literature and analysis of 72 surgically treated patients. Neurosurg Rev 25:155, 2002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Chang EF, Gabriel RA, Potts MB, Berger MS, Lawton MT: Supratentorial cavernous malformations in eloquent and deep locations: surgical approaches and outcomes. Clinical article. J Neurosurg 114:814827, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Del Curling O, Kelly DL, Elster AD, Craven TE: An analysis of the natural history of cavernous angiomas. J Neurosurg 75:702708, 1991

  • 6

    Gross BA, Batjer HH, Awad IA, Bendok BR: Cavernous malformations of the basal ganglia and thalamus. Neurosurgery 65:719, 2009

  • 7

    Gross BA, Batjer HH, Awad IA, Bendok BR, Du R: Brainstem cavernous malformations: 1390 surgical cases from the literature. World Neurosurg 80:8993, 2013

  • 8

    Horne MA, Flemming KD, Su IC, Stapf C, Jeon JP, Li D, : Clinical course of untreated cerebral cavernous malformations: a meta-analysis of individual patient data. Lancet Neurol 15:166173, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Kondziolka D, Lunsford LD, Kestle JR: The natural history of cerebral cavernous malformations. J Neurosurg 83:820824, 1995

  • 10

    Li D, Hao SY, Jia GJ, Wu Z, Zhang LW, Zhang JT: Hemorrhage risks and functional outcomes of untreated brainstem cavernous malformations. J Neurosurg 121:3241, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Li D, Hao SY, Tang J, Xiao XR, Jia GH, Wu Z, : Clinical course of untreated pediatric brainstem cavernous malformations: hemorrhage risk and functional recovery. J Neurosurg Pediatr 13:471483, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Nagy G, McCutcheon BA, Giannini C, Link MJ, Pollock BE: Radiation-induced cavernous malformations after single-fraction meningioma radiosurgery. Oper Neurosurg 15:207212, 2018

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13

    Nagy G, Burkitt W, Stokes SS, Bhattacharyya D, Yianni J, Rowe JG, : Contemporary radiosurgery of cerebral cavernous malformations: Part 1. Treatment outcome for critically located hemorrhagic lesions. J Neurosurg [epub ahead of print July 27, 2018; DOI: 10.3171/2017.5.JNS17776]

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Nagy G, Stokes SS, Erőss LG, Bhattacharyya D, Yianni J, Rowe JG, : Contemporary radiosurgery of cerebral cavernous malformations: Part 2. Treatment outcome for hemispheric lesions. J Neurosurg [epub ahead of print July 27, 2018; DOI: 10.3171/2018.2.JNS171267]

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Taslimi S, Modabbernia A, Amin-Hanjani S, Barker FG, Macdonald RL: Natural history of cavernous malformations: systematic review and meta-analysis of 25 studies. Neurology 86:19841991, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Tian KB, Zheng JJ, Ma JP, Hao SY, Wang L, Zhang LW, : Clinical course of untreated thalamic cavernous malformations: hemorrhage risk and neurological outcomes. J Neurosurg 127:480491, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
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  • 1 National Institute of Clinical Neurosciences, Budapest, Hungary;
  • 2 Thornbury Radiosurgery Centre, Sheffield, United Kingdom; and
  • 3 National Centre for Stereotactic Radiosurgery, Royal Hallamshire Hospital, Sheffield, United Kingdom
Keywords:

Response

Radiosurgery for cavernous malformations (CMs) has been controversial since its introduction. Not only the fact that there is no reliable radiological measure available to indicate cure after radiosurgery, but also the high morbidity associated with the pioneering efforts and ambiguous reports on natural history, has discouraged the neurosurgical community from accepting radiosurgery as a real treatment alternative for a long time. However, while the controversy has lived on, treatments have continued, and at the same time radiosurgery has made technical and perceptual progress, and the natural history and real-life surgical outcomes of patients have become better understood. In this context, we felt it mandatory to analyze data accumulated during the last 2 decades, particularly in light of our current knowledge concerning the natural history and different treatment modalities. The aim of writing our two papers on CM radiosurgery was not only to revisit our increasing pool of data but also to reflect on our current knowledge and to promote open discussion in this context. Therefore, we were happy to read the commentary by Kalani et al. on our papers. While we agree with the authors on some observations, there are strong arguments against some others, and we also have to point out the limitations of our current knowledge that may help us to define future directions.

To start with the weaker part of the CM radiosurgery story, we intentionally wrote a separate paper on hemispheric CMs. As we pointed out in the introduction, hemispheric CMs are not often considered for radiosurgery, because their natural history is less aggressive7 and microsurgical resection is usually safe and effective.4 Moreover, our data suggest that rehemorrhage in this anatomical location does not lead to significantly increased cumulative morbidity. Clearly, for a benign lesion with a 5-year estimated bleeding risk of 3.8% without and 18.4% with prior hemorrhage7 (an annual first-ever hemorrhage rate of 0.6% and rehemorrhage rate of 4.5%),8 the statistical power to detect a significant benefit on hemorrhage rate after radiosurgery remains low. Therefore, even if the radiosurgery-related morbidity is low (6%, all modified Rankin Scale [mRS] score of 1), its role in the prevention of hemorrhage and neurological consequences can rightly be questioned. Ours is an honest paper, clearly pointing out the current limitations of our knowledge in this field, and based on our data, we would strictly reserve radiosurgery for a small group of selected patients harboring proven-aggressive CMs in eloquent locations not amenable to safe resection. There is no doubt that microsurgery is the treatment of choice for most hemispheric hemorrhagic CMs, and we counsel our patients with this knowledge in mind. It should be also stressed, however, that even if the patients are well informed, some would still be reluctant to undergo craniotomy. More importantly, our current paper, together with few prior publications,10 demonstrates that radiosurgery leads to good seizure control similar to microsurgery. Outcomes after both microsurgery and radiosurgery appear to be superior to the natural history or medical therapy alone.3 Thus, as a noninvasive option, radiosurgery can be confidently considered as part of our armamentarium to prevent seizures associated with CMs, especially if the lesion is eloquent, in a patient reluctant to undergo open surgery. It is with this sentiment that we felt it important to bring our results into the public domain.

The second issue is the natural history of deep-seated CMs and the question of whether outcome after radiosurgery is superior to observation in the long term? The most conservative estimate of the 5-year risk of rebleeding from brainstem CMs with a hemorrhagic presentation is 30.8%.7 However, other series give an estimated median hemorrhage-free survival time of 55 months with and 67 months without FNDs of hemorrhagic brainstem CMs,9 and only 55% of thalamic CMs were hemorrhage free at 5 years after presentation.13 Our data suggest a far superior long-term outcome after radiosurgery: the 5-year hemorrhage-free survival is 90% (numbers at risk: 113), falling only to 83% at 10 years (numbers at risk: 43). We accept the argument that our prediction for longer-term outcome becomes uncertain (only 1 patient), but we have to stress that we cannot even provide a prediction of median hemorrhage-free survival after radiosurgery because our data suggest it far later than our observation period (20 years), contrary to the natural history studies. Clearly, more data and a longer follow-up period are needed, but available long-term data are promising.

With regard to the quoted median age at presentation of 37 years and the median age at treatment of 43 years, it is not a real discrepancy between our early intention to treat and our real practice. We would call it, rather, a statistical “illusion” as we state later in the text that the median time between the presenting bleed and radiosurgery was 1 year in the single-bleed group and 3 years in the multiple-bleed group, and the median time between the first and second bleeds was 2 years in the latter group. At first, this may seem paradoxical, but the statistical reason is that the older half of our patients was treated sooner after presentation. In other words, younger patients were relatively older at treatment, which shifted the median time at treatment to older age. In fact, 70% of the single-bleed cohort was treated not later than 1 year after the bleed and 87% within 2 years. From a strict point view, analyzing those single-bleed lesions that were treated within the 1st year after bleed, the annual rate of rebleed was 6% within the first 2 years after radiosurgery and 1% thereafter. These data do not support the “cooling down” theory as a bias. Based on the most conservative estimate, the annual rebleed rate is 15% during the 1st year, 8% during the 2nd year, and 4% thereafter in untreated hemorrhagic brainstem CMs.7 Our data are in line with this trend if we assume a partial protection of radiation during the first 2 years after radiosurgery and a more likely protection thereafter. Moreover, due to partial removal of a significant proportion of surgical cases, the long-term annual rebleed risk is 2% after microsurgery,1 which is clearly not superior to our 1% annual long-term rebleed rate.

The next controversial issue is the morbidity of microsurgery and radiosurgery. It is important to stress that the indications for surgery are restricted, even in the opinion of most experienced surgeons. To quote Dr. Spetzler: “…those that are symptomatic, those that cause mass effect, or those that abut a pial surface” are surgical candidates, and “those with mild symptoms and/or deep-seated CMs were observed until further bleeding episodes made the lesions more amenable to intervention (that is, the pial surface could be reached via the hemorrhagic cavity).”2 This leaves, from our point of view, a broad spectrum of indications for radiosurgery: patients who are without symptoms or with only minimal symptoms and those with deeper-seated, small lesions. If left untreated, only 30% of the patients harboring brainstem lesions recovered fully,9 and only 38% of those with thalamic CMs remained independent.13 We disagree with the policy of waiting until a further bleed destroys enough of the brainstem or thalamus/basal ganglia to become amenable for resection, because it means additional morbidity that is higher than the morbidity of radiosurgery. The rate of functional independence (mRS score of 0 or 1) was 84% before radiosurgery in our cohort of patients with CMs and single hemorrhage, and it remained 78% after radiosurgery, whereas it was 69% and 62% in the multiple bleed group, respectively. Keeping in mind that we are not talking about identical groups of patients, we should point out the dark and not always apparent side of surgery for deep-seated CMs. The authors quote a 36% rate of permanent new deficits with their impressive 260-patient experience in their earlier report of surgical outcome of patients with brainstem CMs,1 while a meta-analysis of 1390 patients indicated only 16% worsening after surgery.6 One wonders about the discrepancy between surgical outcomes in one of the most experienced centers and the rest of the published literature and wonders whether the meta-analysis of the published results is only a reflection of the shiny tip of the iceberg. Admittedly, surgeons do not like to publish their poor results, and our personal perception of the real outcomes of brainstem and thalamic CM surgery (at least in our countries) is certainly closer to (may even be worse than) the 36% surgical morbidity rate of one of the most experienced brainstem surgeons in the world. Moreover, strictly speaking on the shiny published results, 12% of the surgical patients required tracheostomies or gastrostomies, 1.8% of whom required them permanently.6 Even if one does not need them permanently, this is a significant morbidity. We should also consider the socioeconomic costs of microsurgery (including shorter or longer ICU stay) and that nearly half of the microsurgical patients were discharged to an in-patient rehabilitation unit and not home.1 Unfortunately, little information can be found in the literature about the severity of surgical morbidity (in mRS scores), but it is important to stress that the 14.6% overall morbidity rate of radiosurgery indicates an increase of 1 in mRS score in 13.1% of the patients, which means independent life. It is also important to stress that radiosurgery is independent of the operator as it is well standardized even in the case of CMs today. Outcomes are well reproducible all over the world, as it was shown in a recent review of ours: adverse radiation effects of 4.2% and posttreatment hemorrhages of 5.3%.10 From this perspective, one might even consider our present results “poor” in comparison to the radiosurgical literature, but our definition of morbidity was strict and therefore sensitive, and we are still talking about rare minor symptoms in independent patients.

Finally, the authors claim that “radiosurgery is thought to obliterate arteriovenous malformations through a sclerosing action on arteries and arterioles, inducing endothelial cell loss and stimulation of smooth muscle cells,” and CMs “lack these arterial elements, and therefore they lack the biological basis of radiosurgery’s action.” Several histopathological reports demonstrate a “scarring” effect of radiosurgery in CMs11 in parallel to the decreasing rebleed rate, which is not identical to the effect of radiosurgery on arteriovenous malformations.14 It is important to note that these studies were based on specimens from symptomatic patients who underwent surgery after radiosurgery, and therefore it is likely that the histopathological view reflects a partial response in these studies. Nevertheless, the effect of radiosurgery on CMs is already well documented histopathologically.

In conclusion, we agree that CM radiosurgery is still controversial, and there are several concerns to be answered. However, over the last 3 decades the radiosurgical community has been able to define a safe treatment protocol that reduced the initial high morbidity rate seen in the experimental phase, which was the main basis for the early skepticism.5 Moreover, during the last decade, accumulation of extensive population-based data also led to a better understanding of the natural history of CMs, shifting the debate surrounding radiosurgery from a speculative12 to a data- and observation-based foundation. This debate remains ongoing until more data with a higher number of patients and longer follow-up times are available, but we hope that with our present pair of papers we were able to add important pieces of mosaics to the whole picture, and we believe that the current debate will be stimulating for the neurosurgical community.

References

  • 1

    Abla AA, Lekovic GP, Turner JD, de Oliveira JG, Porter R, Spetzler RF: Advances in the treatment and outcome of brainstem cavernous malformation surgery: a single-center case series of 300 surgically treated patients. Neurosurgery 68:403414, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Abla AA, Turner JD, Mitha AP, Lekovic G, Spetzler RF: Surgical approaches to brainstem cavernous malformations. Neurosurg Focus 29(3):E8, 2010

  • 3

    Al-Shahi Salman R: The outlook for adults with epileptic seizure(s) associated with cerebral cavernous malformations or arteriovenous malformations. Epilepsia 53 (Suppl 4):3442, 2012

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4

    Amin-Hanjani S, Ogilvy CS, Ojemann RG, Crowell RM: Risks of surgical management for cavernous malformations of the nervous system. Neurosurgery 42:12201228, 1998

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Bertalanffy H, Benes L, Miyazawa T, Alberti O, Siegel AM, Sure U: Cerebral cavernomas in the adult. Review of the literature and analysis of 72 surgically treated patients. Neurosurg Rev 25:155, 2002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Gross BA, Batjer HH, Awad IA, Bendok BR, Du R: Brainstem cavernous malformations: 1390 surgical cases from the literature. World Neurosurg 80:8993, 2013

  • 7

    Horne MA, Flemming KD, Su IC, Stapf C, Jeon JP, Li D, : Clinical course of untreated cerebral cavernous malformations: a meta-analysis of individual patient data. Lancet Neurol 15:166173, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Kondziolka D, Lunsford LD, Kestle JR: The natural history of cerebral cavernous malformations. J Neurosurg 83:820824, 1995

  • 9

    Li D, Hao SY, Jia GJ, Wu Z, Zhang LW, Zhang JT: Hemorrhage risks and functional outcomes of untreated brainstem cavernous malformations. J Neurosurg 121:3241, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Nagy G, Kemeny AA: Radiosurgery for cerebral cavernomas. J Neurosurg Sci 59:295306, 2015

  • 11

    Shin SS, Murdoch G, Hamilton RL, Faraji AH, Kano H, Zwagerman NT, : Pathological response of cavernous malformations following radiosurgery. J Neurosurg 123:938944, 2015

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    • Search Google Scholar
    • Export Citation
  • 12

    Steiner L, Karlsson B, Yen CP, Torner JC, Lindquist C, Schlesinger D: Editorial. Radiosurgery in cavernous malformations: anatomy of a controversy. J Neurosurg 113:1622, 2010

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    • Search Google Scholar
    • Export Citation
  • 13

    Tian KB, Zheng JJ, Ma JP, Hao SY, Wang L, Zhang LW, : Clinical course of untreated thalamic cavernous malformations: hemorrhage risk and neurological outcomes. J Neurosurg 127:480491, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Tu J, Stoodley MA, Morgan MK, Storer KP, Smee R: Different responses of cavernous malformations and arteriovenous malformations to radiosurgery. J Clin Neurosci 16:945949, 2009

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    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

Contributor Notes

Correspondence M. Yashar S. Kalani: kalani@virginia.edu.

INCLUDE WHEN CITING Published online October 19, 2018; DOI: 10.3171/2018.8.JNS182284.

Disclosures The authors report no conflict of interest.

  • 1

    Abla AA, Lekovic GP, Turner JD, de Oliveira JG, Porter R, Spetzler RF: Advances in the treatment and outcome of brainstem cavernous malformation surgery: a single-center case series of 300 surgically treated patients. Neurosurgery 68:403415, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Amin-Hanjani S, Ogilvy CS, Ojemann RG, Crowell RM: Risks of surgical management for cavernous malformations of the nervous system. Neurosurgery 42:12201228, 1998

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Bertalanffy H, Benes L, Miyazawa T, Alberti O, Siegel AM, Sure U: Cerebral cavernomas in the adult. Review of the literature and analysis of 72 surgically treated patients. Neurosurg Rev 25:155, 2002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Chang EF, Gabriel RA, Potts MB, Berger MS, Lawton MT: Supratentorial cavernous malformations in eloquent and deep locations: surgical approaches and outcomes. Clinical article. J Neurosurg 114:814827, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Del Curling O, Kelly DL, Elster AD, Craven TE: An analysis of the natural history of cavernous angiomas. J Neurosurg 75:702708, 1991

  • 6

    Gross BA, Batjer HH, Awad IA, Bendok BR: Cavernous malformations of the basal ganglia and thalamus. Neurosurgery 65:719, 2009

  • 7

    Gross BA, Batjer HH, Awad IA, Bendok BR, Du R: Brainstem cavernous malformations: 1390 surgical cases from the literature. World Neurosurg 80:8993, 2013

  • 8

    Horne MA, Flemming KD, Su IC, Stapf C, Jeon JP, Li D, : Clinical course of untreated cerebral cavernous malformations: a meta-analysis of individual patient data. Lancet Neurol 15:166173, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Kondziolka D, Lunsford LD, Kestle JR: The natural history of cerebral cavernous malformations. J Neurosurg 83:820824, 1995

  • 10

    Li D, Hao SY, Jia GJ, Wu Z, Zhang LW, Zhang JT: Hemorrhage risks and functional outcomes of untreated brainstem cavernous malformations. J Neurosurg 121:3241, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
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