Clinical course of untreated cerebral cavernous malformations: individual patient data meta-analysis

Horne, Margaret; Flemming, Kelly D.; Su, I‐Chang; Stapf, Christian; Brown, Robert; Christianson, Teresa J.H.; Agid, Ronit; terBrugge, Karel G.; Willinsky, Robert A.; Maxwell, Susanne; Murray, Gordon; Salman, Rustam Al-Shahi

doi:10.1186/1745-6215-14-s1-p118

Cited by 46 publications

(121 citation statements)

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“…Yet it is unclear at what stage, and for how long a human lesion should be treated in order to prevent bleeding or rebleeding. It may be compelling to consider drug therapy for a lesion that has recently bled, and is hence most likely to rebleed in the next 2-3 years, 54, 55 so ROCK inhibition might be conceived as lesion stabilization therapy. Dose escalation in clinical trials may be calibrated using dynamic contrast enhanced quantitative perfusion on MRI, thought to reflect ROCK induced hyperpermeability in vivo.…”

Section: Discussionmentioning

confidence: 99%

RhoA Kinase Inhibition With Fasudil Versus Simvastatin in Murine Models of Cerebral Cavernous Malformations

Shenkar

Shi

Austin

et al. 2017

Stroke

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Background and Purpose We sought to compare the effect of chronic treatment with commonly tolerated doses of Fasudil, a specific RhoA kinase (ROCK) inhibitor, and simvastatin (with pleiotropic effects including ROCK inhibition) on cerebral cavernous malformation (CCM) genesis and maturation in two models that recapitulate the human disease. Methods Two heterozygous murine models, Ccm1+/-Msh2-/- and Ccm2+/-Trp53-/-, were treated from weaning to 4-5 months of age with Fasudil (100 mg/kg/day), simvastatin (40 mg/kg/day) or with placebo. Mouse brains were blindly assessed for CCM lesion burden, non-heme iron deposition (as a quantitative measure of chronic lesional hemorrhage) and ROCK activity. Results Fasudil, but not simvastatin, significantly decreased mature CCM lesion burden in Ccm1+/-Msh2-/- mice, and in meta-analysis of both models combined, when compared to mice receiving placebo. Fasudil and simvastatin both significantly decreased the integrated iron density per mature lesion area in Ccm1+/-Msh2-/- mice, and in both models combined, compared to mice given placebo. ROCK activity in mature lesions of Ccm1+/-Msh2-/- mice was similar with both treatments. Fasudil, but not simvastatin, improved survival in Ccm1+/-Msh2-/- mice. Fasudil and simvastatin treatment did not affect survival or lesion development significantly in Ccm2+/-Trp53-/- mice alone, and Fasudil benefit appeared limited to males. Conclusion ROCK inhibitor Fasudil was more efficacious than simvastatin in improving survival and blunting the development of mature CCM lesions. Both drugs significantly decreased chronic hemorrhage in CCM lesions. These findings justify the development of ROCK inhibitors, and the clinical testing of commonly used statin agents in CCM.

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Section: Discussionmentioning

confidence: 99%

RhoA Kinase Inhibition With Fasudil Versus Simvastatin in Murine Models of Cerebral Cavernous Malformations

Shenkar

Shi

Austin

et al. 2017

Stroke

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“…On T2‐weighted magnetic resonance imaging (MRI), CCMs appear heterogeneously hyperintense with a surrounding hypointense rim of hemosiderin‐laden parenchyma. CCMs are relatively common (incidence of 0.16%) and carry a 5‐year symptomatic hemorrhage risk of 15.8% . CCMs cause gliosis and neuronal irritation; up to 70% of patients with supratentorial CCMs present with seizures, and 40%‐50% of these cases become medically refractory …”

Section: Introductionmentioning

confidence: 99%

“…CCMs are relatively common (incidence of 0.16% 3 ) and carry a 5-year symptomatic hemorrhage risk of 15.8%. [4][5][6][7] CCMs cause gliosis and neuronal irritation 8,9 ; up to 70% of patients with supratentorial CCMs present with seizures, and 40%-50% of these cases become medically refractory. 2,10,11 Surgical resection of a CCM and surrounding cortex is considered critical to achieving seizure freedom.…”

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confidence: 99%

Safety and effectiveness of stereotactic laser ablation for epileptogenic cerebral cavernous malformations

et al. 2019

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Summary Objective Magnetic resonance (MR) thermography–guided laser interstitial thermal therapy, or stereotactic laser ablation (SLA), is a minimally invasive alternative to open surgery for focal epilepsy caused by cerebral cavernous malformations (CCMs). We examined the safety and effectiveness of SLA of epileptogenic CCMs. Methods We retrospectively analyzed 19 consecutive patients who presented with focal seizures associated with a CCM. Each patient underwent SLA of the CCM and adjacent cortex followed by standard clinical and imaging follow‐up. Results All but one patient had chronic medically refractory epilepsy (median duration 8 years, range 0.5‐52 years). Lesions were located in the temporal (13), frontal (five), and parietal (one) lobes. CCMs induced magnetic susceptibility artifacts during thermometry, but perilesional cortex was easily visualized. Fourteen of 17 patients (82%) with >12 months of follow‐up achieved Engel class I outcomes, of which 10 (59%) were Engel class IA. Two patients who were not seizure‐free from SLA alone became so following intracranial electrode‐guided open resection. Delayed postsurgical imaging validated CCM involution (median 83% volume reduction) and ablation of surrounding cortex. Histopathologic examination of one previously ablated CCM following open surgery confirmed obliteration. SLA caused no detectable hemorrhages. Two symptomatic neurologic deficits (visual and motor) were predictable, and neither was permanently disabling. Significance In a consecutive retrospective series, MR thermography–guided SLA was an effective alternative to open surgery for epileptogenic CCM. The approach was free of hemorrhagic complications, and clinically significant neurologic deficits were predictable. SLA presents no barrier to subsequent open surgery when needed.

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“…Horne et al make a very important contribution to our knowledge of the natural history of cavernous malformations 1 , providing robust evidence for long-held suspicions that brainstem location and hemorrhagic lesions portend a more aggressive clinical course. When observed together, these lesions have an estimated 5-year recurrent hemorrhage risk of 30.8%, with a 50.7% risk of developing either a recurrent hemorrhage or a new neurological deficit not related to hemorrhage.…”

Section: Introductionmentioning

confidence: 99%

Brainstem cavernous malformations: Natural history versus surgical management

Walcott

Choudhri

Lawton

2016

Journal of Clinical Neuroscience

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While brainstem cavernous malformations were once considered inoperable, improvements in patient selection, surgical exposures, intraoperative MRI-guidance, MR tractography, and neurophysiologic monitoring have resulted in good outcomes in the majority of operated patients. In a consecutive series of 104 patients with brainstem cavernous malformations, only 14% of patients experienced cranial nerve or motor dysfunction that was worse at late follow-up, relative to their preoperative condition. Outcomes were predicted by several factors, including larger lesion size, lesions that crossed midline, the presence of a developmental venous anomaly, older age, and greater time interval from lesion hemorrhage to surgery. The 14% of patients who experienced a persistent neurological deficit as a result of surgery, while substantial from any perspective, compares favorably with the risks of observation based on a meta-analysis published by Horne et al. 2016. Curative resection is a safe and effective treatment for brainstem cavernous malformations that will prevent re-hemorrhage in symptomatic patients.

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Clinical course of untreated cerebral cavernous malformations: individual patient data meta-analysis

Cited by 46 publications

References 0 publications

RhoA Kinase Inhibition With Fasudil Versus Simvastatin in Murine Models of Cerebral Cavernous Malformations

RhoA Kinase Inhibition With Fasudil Versus Simvastatin in Murine Models of Cerebral Cavernous Malformations

Safety and effectiveness of stereotactic laser ablation for epileptogenic cerebral cavernous malformations

Brainstem cavernous malformations: Natural history versus surgical management

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