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Accepted Manuscript Propranolol treatment of cavernous malformations with symptomatic hemorrhage Joseph M. Zabramski, MD, M. Yashar S. Kalani, MD, PhD, Aristotelis S. Filippidis, MD, Robert F. Spetzler, MD PII:

S1878-8750(15)01517-X

DOI:

10.1016/j.wneu.2015.11.003

Reference:

WNEU 3394

To appear in:

World Neurosurgery

Received Date: 14 September 2015 Revised Date:

2 November 2015

Accepted Date: 3 November 2015

Please cite this article as: Zabramski JM, Kalani MYS, Filippidis AS, Spetzler RF, Propranolol treatment of cavernous malformations with symptomatic hemorrhage, World Neurosurgery (2015), doi: 10.1016/ j.wneu.2015.11.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Zabramski JM et al. 1

Joseph M. Zabramski, MD M. Yashar S. Kalani, MD, PhD Aristotelis S. Filippidis, MD

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Robert F. Spetzler, MD

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Propranolol treatment of cavernous malformations with symptomatic hemorrhage

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Department of Neurosurgery

Barrow Neurological Institute

St. Joseph’s Hospital and Medical Center

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Phoenix, Arizona

Correspondence: Joseph M. Zabramski, MD c/o Neuroscience Publications; Barrow Neurological Institute

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St. Joseph’s Hospital and Medical Center

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350 W. Thomas Rd.; Phoenix, AZ 85013 Tel: 602.406.3593; Fax: 602.406.4104 E-mail: [email protected]

DISCLOSURES: None

FINANCIAL ASSISTANCE: None

ACCEPTED MANUSCRIPT Zabramski JM et al. 2 ACKNOWLEDGMENTS: The authors would like to thank the Neuroscience Publications staff

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at Barrow Neurological Institute for their assistance in preparing this manuscript.

ACCEPTED MANUSCRIPT Zabramski JM et al. 3 ABSTRACT Background: Cerebral cavernous malformations are more common than generally thought, affecting approximately 1 in every 250 adults. Most of these lesions are asymptomatic or have a

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relatively benign course, but a small minority behave aggressively and present with recurrent episodes of symptomatic hemorrhage. A safe and effective medical treatment option for the management of this latter group would be useful. Propranolol has recently been shown to be

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effective in the treatment of infantile hemangioma, a close pathologic counterpart of cavernous malformations. These results suggest a potential role for propranolol treatment in the

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management of patients with symptomatic cavernous malformations.

Methods: Low-dose propranolol (20 mg, three times daily) was used to treat two adult patients, a 54-year-old woman and a 57-year-old woman, who had symptomatic cavernous malformations and a history of repeated hemorrhage. Serial magnetic resonance imaging studies after the

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initiation of propranolol demonstrated regression of the lesions and no evidence of recurrent hemorrhage.

Conclusions: Propranolol may offer a safe and effective treatment for patients who have

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cavernous malformations with symptomatic hemorrhage. Additional studies are needed to

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confirm these findings.

KEYWORDS: Beta-blockers; cavernous malformations; cerebral cavernous malformations; hemorrhage; propranolol; symptomatic RUNNING TITLE: Propranolol treatment of cavernous malformations

ACCEPTED MANUSCRIPT Zabramski JM et al. 4 ABBREVIATIONS CCM, cerebral cavernous malformation

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SUBMISSION CATEGORY: Original Article

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MRI, magnetic resonance imaging

ACCEPTED MANUSCRIPT Zabramski JM et al. 5 HIGHLIGHTS Cerebral cavernous malformations (CCMs) affect approximately 0.4% of the population



Effective treatment of symptomatic CCMs typically requires surgical resection



Propranolol has been shown to be effective in the treatment of infantile hemangiomas



CCMs are close pathologic counterparts of hemangiomas



Treatment of symptomatic CCMs with propranolol may be an alternative to surgery

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ACCEPTED MANUSCRIPT Zabramski JM et al. 6 INTRODUCTION Surgical resection is the primary mode of treatment for cerebral cavernous malformations (CCMs) in patients who present with recurrent symptomatic hemorrhage. Although surgery for

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superficial hemispheric lesions is typically well tolerated, the resection of deep lesions involving the brainstem and basal ganglia can be daunting, and has been associated with high risk for new deficits.1 An effective medical treatment that reduces or eliminates the risks of hemorrhage in

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patients with deep symptomatic CCMs would be invaluable.

Recent reports have documented clinically significant benefit for treatment with the beta-

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blocker propranolol in the management of aggressive infantile hemangioma.2, 3 Pathologically, cavernous malformations are closely related to hemangiomas, and the terms cavernous malformation and cavernous hemangioma are often used interchangeably in the medical literature describing these lesions.4, 5 Propranolol is inexpensive and well tolerated in both

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children and adults.

We describe two adult patients with symptomatic CCMs, in whom the administration of

CASE 1

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low-dose oral propranolol appears to have ameliorated the risk of recurrent hemorrhage.

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The patient is a 59-year-old woman with a well-documented history of familial CCMs

She is well known to the senior authors (J.M.Z. and R.F.S.) having previously undergone surgical resection of a symptomatic right posterior frontal lobe cavernous malformation in 1990 at 34 years of age. She made a good recovery from surgery, and was subsequently enrolled in our prospective Natural History of Familial Cavernous Malformations study. In 1998 a routine magnetic resonance imaging (MRI) scan was negative for any evidence of new lesions (Fig. 1A);

ACCEPTED MANUSCRIPT Zabramski JM et al. 7 however, in 2008 a repeat MRI demonstrated development of two asymptomatic de novo CCMs; the first in the left corona radiata, and the second in the left occipital lobe (Fig. 1B). Two years later, in October 2010 the patient presented with complaints of new-onset numbness in the right

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lower extremity, An MRI scan revealed a 2.25-cm focus of acute and subacute hemorrhage in the left corona radiata lesion (Fig. 1C). Imaging characteristics were consistent with gross

hemorrhage extending outside the lesion capsule, with focal edema adjacent to the region of

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hemorrhage (Type 1a lesion; Table 1). Symptoms rapidly resolved and the patient was followed conservatively. Follow-up imaging 5 months later in March 2011 demonstrated an interval

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decrease in the size of the lesion. In November 2011, approximately 1 year after the first episode of symptomatic hemorrhage, the patient complained of recurrent numbness and headaches; repeat MRI demonstrated a second new focus of extralesional hemorrhage and edema (Fig. 1D). The patient was extremely reluctant to consider surgical intervention, and instead was started on

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a trial of propranolol 20 mg three times daily. Follow-up imaging in March 2013, 14 months after initiation of propranolol therapy, revealed marked reduction in the size of the previously hemorrhagic lesion, with characteristic MRI findings of only chronic hemorrhage (Fig. 1E). The

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patient’s dose of propranolol was reduced to 20 mg two times daily for 1 year and then discontinued; she has remained asymptomatic with no evidence of repeat hemorrhage on a recent

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MRI scan obtained in February 2015 (Fig. 1F). Gradient-echo images from this most recent MRI demonstrated innumerable CCMs characteristic for the familial form of this disease (Fig. 1G).

CASE 2

The patient is a 57-year-old woman initially seen in neurosurgical consultation in May 2013 for management of a large left occipital lobe cavernous malformation. She reported a 6-

ACCEPTED MANUSCRIPT Zabramski JM et al. 8 year history of severe headaches. MRI scans in April 2008 and in February 2009 were remarkable only for mild bilateral periventricular white matter changes consistent with smallvessel disease (Fig. 2A). In February 2011, she had an exacerbation of her usual headache

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pattern, and a repeat MRI scan demonstrated the de novo appearance of a cavernous

malformation in the left occipital lobe, measuring 1.3× 1.5×1.2 cm (Fig. 2B). In November 2011 she noted the onset of a partial right upper quadrant visual field defect, and follow-up MRI

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revealed new areas of acute and subacute hemorrhage with a resultant doubling in the size of the lesion to 2.3×3.1×2.3 cm (Fig. 2C). Additional areas of hemorrhage were identified on repeat

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imaging in April 2012 (Fig. 2D) and in January 2013 (Fig. 2E). In April 2013, the patient’s visual deficit progressed to a complete right upper quadrantanopia; repeat imaging demonstrated evidence of gross hemorrhage with surrounding edema (Type 1a lesion; Table 1), with the lesion now measuring 3.7×5.2×3.0 cm (Fig. 2F). Surgical intervention was recommended, but the

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patient was unwilling to risk additional visual impairment, and declined. She was started on a trial of propranolol 20 mg three times daily, and follow-up imaging 3 months later in July 2013 demonstrated a 40% decrease in the size of the lesion to 2.7×4.4×2.9 cm (Fig. 2G). In January

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2014, a repeat MRI scan obtained 9 months after initiation of propranolol revealed that the lesion had regressed to a Type 2 CCM, with a further decrease in size to 1.9×2.8×2.6 cm and resolution

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of all surrounding edema (Fig. 2H).

The patient suffered from morbid obesity (body mass index, 48.7). She reported that

taking the propranolol caused shortness of breath and markedly decreased her exercise tolerance, such that even short walks of 150 feet were difficult without frequent stops to rest. In June 2014, she was hospitalized after she fell and dislocated her shoulder; a repeat MRI scan demonstrated no change in the size or imaging characteristics of the CCM (Fig. 2I). She called to discuss the

ACCEPTED MANUSCRIPT Zabramski JM et al. 9 fall, which she attributed to the side effects of propranolol, and her dose was subsequently reduced to 20 mg twice daily. Despite this dose reduction, she continued to experience shortness of breath and exercise intolerance and discontinued her propranolol completely on October 1,

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2014. She subsequently noted improved breathing and exercise tolerance, but began suffering from severe headaches again.

In December 2014, a repeat MRI scan 3 months after the propranolol was discontinued

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revealed significant enlargement of the CCM, with several new foci of acute/subacute hemorrhage and surrounding edema, with the lesion having increased in size again to

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2.6×3.3×3.4 cm (Fig. 2J). In January 2015, unable to tolerate propranolol, the patient agreed to surgical resection. A preoperative MRI scan, performed in February 2015, only 7 weeks after the December study, demonstrated additional new areas of hemorrhage and increased edema (Fig. 2K). The day after this study, the patient underwent a stereotactic-guided left occipital

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craniotomy and trans-sulcal resection of the cavernous malformation. She tolerated this procedure well, with no increase in her visual deficits. A same-day postoperative MRI scan showed complete resection of the lesion (Fig. 2L). The final pathologic diagnosis of the resected

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DISCUSSION

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specimen was cavernous malformation.

CCMs are the most common type of vascular malformation, with a reported prevalence

of 0.34% to 0.53% (mean, 0.47%), affecting approximately 1 in every 250 individuals.6-10 CCMs occur throughout the central nervous system in rough proportion to the volume of the various compartments; 80% supratentorial, 15% brainstem and basal ganglia, and 5% spinal cord.

ACCEPTED MANUSCRIPT Zabramski JM et al. 10 Although CCMs were once thought to be congenital in origin, there are now numerous reports of the de novo formation of CCMS in both spontaneous and familial forms of the disease.11-22 Evidence of previous hemorrhage on MRI scans is a diagnostic feature of all CCMs,

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regardless of whether or not the lesions are symptomatic. Hemorrhages at various ages within the lesions, in combination with the deposition of hemosiderin in the surrounding parenchyma, produces the unique MRI characteristics of these lesions.23, 24

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Because CCMs are low-flow, low-pressure lesions, hemorrhages, even so-called overt hemorrhages that extend outside the lesion capsule, tend to displace and compress adjacent

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neural tissue rather than destroy it. Symptoms associated with hemorrhage from CCMs are related to the lesion location. Patients commonly present with seizures when lesions are located in the cerebral hemispheres, while patients with hemorrhages in CCMs located in the basal ganglia, brainstem, or spinal cord typically present with focal neurological deficits.

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The risk of symptomatic hemorrhage from CCMs has been shown to be related to their presentation (asymptomatic vs. symptomatic),25, 26 as well as to the location of the lesion (superficial vs. deep).27 Not surprisingly, hemorrhage is more likely to lead to symptoms when

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lesions are located in the basal ganglia and brainstem. A conservative estimate, based on the assumption that lesions are present from birth to the first symptom, places the risk for a first

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symptomatic hemorrhage in the range of 2.5% to 8.7% per lesion-year (mean, 4.5% per lesionyear).28-36 For patients with a history of previous symptomatic hemorrhage, the risk of rebleeding ranges from 5.1% to 60% per lesion-year (mean, 29.8%), with higher rates reported in surgical series.28-31, 33-36

The risk of hemorrhage also appears to be related to the MRI characteristics of the lesion. Zabramski et al have previously published an MRI grading scale for CCMs, dividing lesions into

ACCEPTED MANUSCRIPT Zabramski JM et al. 11 four major groups (Table 1).12, 37 Symptomatic hemorrhage occurs most commonly in patients with Type 1 and Type 2 lesions.8, 38-41 The risk of hemorrhage appears to be highest in patients who present with overt hemorrhage that extends outside the lesion capsule (Type 1a, Table 1).

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Episodes of overt hemorrhage are characterized on MRI by the presence of mass effect and/or edema in the surrounding brain. (Figs. 1C, 2E, 2F). Aiba and colleagues monitored a group of 62 such patients for a mean of 3.12 years and noted a risk for recurrent symptomatic hemorrhage of

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22.3% per lesion-year.26 Barker and colleagues reported similar findings in 141 patients selected for intervention who had overt hemorrhages.39 In their series, 63 patients experienced a second

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hemorrhage before treatment. Hemorrhages clustered around the initial event, with a repeat hemorrhage rate of 25.2% per year for the first 28 months.

The present options for the management of patients with symptomatic CCMs are limited. Observation may be a reasonable option for patients who present with a history of seizures,

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particularly if the seizures are well controlled. When patients present with poorly controlled seizures, or new episodes of symptomatic hemorrhage from deep lesions, surgical resection is typically recommended. Although microsurgical resection of CCMs can be performed with

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relative safety for most superficial lesions, surgery for lesions located deep in the basal ganglia or brainstem is associated with high rates of morbidity.1, 30, 42, 43 Experienced neurosurgeons

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report complication rates of 12% to 36% for permanent new deficits in patients who undergo resection of brainstem CCMs.30, 35, 42, 43 Observation is not without risk in this group, as the incidence of recurrent hemorrhage ranges from 32% to 61%.30, 35, 43 Treatment with stereotactic radiosurgery has had mixed success, with some authors

reporting significant benefit; however, this form of therapy has the distinct disadvantage of a roughly 2-year latency period before the risk of hemorrhage is significantly reduced.44-49 In

ACCEPTED MANUSCRIPT Zabramski JM et al. 12 addition, this therapy is generally limited to small lesions with treatment volumes of less than 2 to 3 cubic centimeters. A safe and effective systemic treatment that reduces or eliminates the risks of recurrent

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hemorrhage is needed. Several groups have recently investigated the potential for using small molecules to treat CCMs in preclinical studies. Li and Whitehead documented the role of RhoA hyperactivation in the pathophysiology of CCMs and proposed statins as a therapeutic option for

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CCMs.50 Similarly, the Rho kinase inhibitor fasudil has been investigated as a potential treatment option.51

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In 2010 Moschovi et al52 published a report describing the oral administration of 2 mg/kg per day of propranolol for treatment of a giant CCM in a 7-month-old infant. The lesion demonstrated a significant decrease in size after 10 days of propranolol treatment and was subsequently resected. The rational for a trial of propranolol treatment was a 2008 report by

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Leaute-Labreze and colleagues describing the effectiveness of oral propranolol at 2 mg/kg per day for the treatment of severe cutaneous infantile hemangiomas.53 The common histopathological background shared by CCMs and cutaneous capillary hemangiomas4, 5

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suggested that CCMs might have a similar response to propranolol. Two additional brief reports have since appeared in the pediatric literature describing the administration of oral propranolol (3

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mg/kg/day) in an 8-day-old54 and (2 mg/kg/day) in a 15-month-old infant55 for the treatment of multiple CCMs with MRI evidence of gross hemorrhage. In both cases propranolol treatment resulted in rapid improvement in imaging findings. The underlying pathophysiological mechanisms explaining the action of propranolol in the treatment of hemangiomas include the 1) induction of vasoconstriction; 2) decreased expression of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenic

ACCEPTED MANUSCRIPT Zabramski JM et al. 13 factors; 3) triggering of an apoptotic process in the capillary endothelial cells; 4) inhibition of tubulogenesis in brain endothelial cells; and 5) suppression of proliferation, migration, and differentiation of endothelial cells.56-59

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Propranolol is a low-cost medication with a long history of widespread clinical use. It has been approved by the European Medicines Agency and the U.S. Food and Drug Administration. Propranolol has a remarkably safe clinical profile for systemic administration, especially

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compared to fasudil and HMG-CoA reductase inhibitors, with a recent large trial of its use for infantile hemangioma documenting no evidence of complications.2 These properties indicate that

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propranolol could potentially be an ideal candidate for treating symptomatic CCMs of the central nervous system.28

Previous publications describing the efficacy of propranolol in the treatment of capillary hemangioma and CCMs have documented its use in infants. In this report, we describe the

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results of propranolol treatment of CCMs in two adults. Low-dose oral propranolol (20 mg three times daily) appeared to ameliorate the risk of recurrent symptomatic hemorrhage. Both patients had suffered multiple hemorrhages from their CCMs. MRI demonstrated findings of overt

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hemorrhage extending outside the lesion capsule, with associated perilesional edema in both patients (Type 1a lesion, Table 1). These imaging characteristics are associated with a high risk

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of recurrent hemorrhage of up to 60% per year, with a mean of 25% to 30% per year). In the second patient (Case 2), repeated hemorrhages over a 2-year interval resulted in a 25-fold increase in the volume of the CCM from 1.2 mL to 28.9 mL. After initiation of propranolol therapy, the hemorrhages ceased, and during the 14-month interval that the patient took propranolol, the lesion regressed 76% in volume to 6.9 mL. More importantly, within 3 months of discontinuing propranolol therapy, the patient once again experienced severe headaches, and

ACCEPTED MANUSCRIPT Zabramski JM et al. 14 repeat MRI scans demonstrated evidence of multiple new hemorrhages with rapid growth. This latter history substantially strengthens the case for a cause-and-effect relationship for a beneficial role of propranolol in the management of this patient’s CCM.

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While these results are encouraging, we cannot exclude the possibility that the

observations in these patients are a reflection of the natural history of CCMs and chance. Cavernous malformations are dynamic lesions, and spontaneous regression secondary to

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reabsorption of hematoma between bleeding episodes has been well described. Confirmation of the role of propranolol in the treatment of symptomatic cavernous malformations by others is

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needed. Proof of efficacy will ultimately require a randomized controlled trial.

CONCLUSION

Propranolol treatment appears to ameliorate the risk of recurrent hemorrhage in infants

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and adults with symptomatic CCMs, suggesting that propranolol may offer a safe and effective alternative/adjunct to surgical intervention in select patients. Additional studies are needed to

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confirm these findings.

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ACCEPTED MANUSCRIPT Zabramski JM et al. 23 FIGURE LEGENDS Figure 1. Sequential T2-weighted magnetic resonance imaging (MRI) scans of a 59-year-old woman (case 1) with a history of familial cavernous malformations. (A) A routine MRI scan in

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September 1998 reveals several punctate foci of low-signal intensity consistent with Type 3 CCMs (arrows). (B) A follow-up MRI scan in September 2008 demonstrates the de novo

appearance of two Type 2 CCMs (arrows); one in the left corona radiate adjacent to the ventricle,

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and another in the left occipital lobe. Two years later the patient noted the sudden onset of

numbness in the right lower extremity, and (C) a repeat MRI scan in October 2010 revealed

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conversion of the left periventricular CCM to a Type 1a lesion with a focus of subacute hemorrhage that extended outside the lesion capsule (arrows), surrounded by edema (arrowheads). (D) An MRI scan obtained approximately 1 year later in November 2011 demonstrates another new focus of extralesional hemorrhage in the left periventricular CCM

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(arrows). After initiation of oral treatment with propranolol, follow-up imaging (E) in March 2013 and (F) in February 2015 demonstrate regression of the symptomatic cavernous malformation to a Type 2 lesion with no evidence of recurrent hemorrhage. (G) Gradient-echo

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imaging performed in February 2015 demonstrates innumerable asymptomatic Type 4 CCMs scattered throughout the brainstem, cerebellum, and cerebral hemispheres, consistent with the

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diagnosis of familial CCM. Used with permission from Barrow Neurological Institute, Phoenix, Arizona.

Figure 2. Sequential T2-weighted magnetic resonance imaging (MRI) scans of a 57-year-old woman (case 2) with spontaneous de novo development of a left occipital lobe CCM.(A) An MRI scan performed in February 2009 for evaluation of severe headaches reveals no abnormal findings. (B) A repeat MRI scan performed in February 2011 for exacerbation of headaches

ACCEPTED MANUSCRIPT Zabramski JM et al. 24 demonstrates de novo development of a Type 2 CCM (arrows) in the left occipital lobe. (C) An MRI scan performed in November 2011 for new visual complaints reveals new areas of hemorrhage within the occipital lobe CCM and resultant doubling in the size of the lesion. (D)

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Follow-up imaging in April 2012 demonstrates an additional focus of subacute hemorrhage (arrows). (E) An MRI scan obtained approximately 9 months later in January 2013 reveals

further hemorrhage and growth of the lesion, with the appearance of edema (arrowheads) in the

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surrounding brain, consistent with hemorrhage outside the lesion capsule and conversion to a Type 1a CCM. (F) Repeat imaging 3 months later in April 2013 for progression of visual

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symptoms shows further enlargement of the lesion with multiple new foci of extralesional hemorrhage (arrows) and extensive surrounding edema. (G) In July 2013, a follow-up MRI scan 3 months obtained after initiation of propranolol therapy demonstrates a decrease in the size of the lesion with contraction of the previous foci of hemorrhage and a reduction in the surrounding

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edema. (H) In January 2014, a repeat MRI scan 9 months after initiation of propranolol therapy reveals further contraction of the lesion, with no evidence of recurrent hemorrhage, which is once again consistent with a Type 2 CCM. (I) An MRI scan in June 2014 shows no change from

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the previous study. (J) An MRI scan obtained 3 months later in December 2014 after the patient had discontinued propranolol therapy in October 2014 reveals new foci of subacute extralesional

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hemorrhage (arrows) and recurrent perilesional edema (arrowheads). (K) In February 2015, after propranolol therapy had been discontinued 5 months earlier, a preoperative MRI scan demonstrates further hemorrhage (arrow) and expansion of the lesion. (L) T1-weighted images from a postoperative MRI scan performed on the day of surgery confirm complete resection of the CCM. Used with permission from Barrow Neurological Institute, Phoenix, Arizona.

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Table 1. Magnetic Resonance Imaging Classification of Cavernous Malformations MR Signal Characteristic Pathologic Characteristics Lesion Type

Type 2

Loculated areas of hemorrhage and thrombosis of varying age, surrounded by gliotic, hemosiderin-stained brain; large lesions may contain areas of calcification Chronic resolved hemorrhage with hemosiderin staining within and around lesion

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T1: Reticulated mixed signal core T2: Reticulated mixed signal core surrounded by a hypointense rim (Fig. 1B and 1F; Fig. 2B)

Subacute focus of intralesional hemorrhage

Risk of symptomatic hemorrhage related to presentation and location. Higher for symptomatic lesions in the brainstem and basal ganglia (10-20% per year); lower in asymptomatic lesions. Risk of symptomatic hemorrhage related to presentation. Risk of recurrent hemorrhage is 4-5% per year in symptomatic patients and 0.5-1% per year in asymptomatic patients. Rarely symptomatic. Lesions have a low risk of hemorrhage (

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