Symptomatic Brain Hemorrhages from Cavernous Angioma After Botulinum Toxin Injections, a Role of TLR/MEKK3 Mechanism? Case Report and Review of the Literature.

BACKGROUND: Cavernous angiomas (CAs) are vascular malformations that may result in stroke. CASE DESCRIPTION: Herein, we evaluate a CA patient with chronic migraine who experienced 2 documented symptomatic hemorrhages after receiving respective high doses of botulinum toxin (Btx). CONCLUSIONS: Recently, bacterial lipopolysaccharide has been reported to contribute to CA development through Toll-like receptor signaling, causing hemorrhagic angiogenic proliferation. Lipopolysaccharide and Btx share a common intracellular signaling pathway driving CA development and hemorrhage. Significance of these observations is demonstrated by previous works on plasma molecules showing prognostic associations with symptomatic hemorrhages in human CA, related to the same canonical pathways. Authors suggest careful tracking of the association of Btx and hemorrhage in CA patients.

A Brain-Targeted Orally Available ROCK2 Inhibitor Benefits Mild and Aggressive Cavernous Angioma Disease.

Cavernous angioma (CA) is a vascular pathology caused by loss of function in one of the 3 CA genes (CCM1, CCM2, and CCM3) that result in rho kinase (ROCK) activation. We investigated a novel ROCK2 selective inhibitor for the ability to reduce brain lesion formation, growth, and maturation. We used genetic methods to explore the use of a ROCK2-selective kinase inhibitor to reduce growth and hemorrhage of CAs. The role of ROCK2 in CA was investigated by crossing Rock1 or Rock2 hemizygous mice with Ccm1 or Ccm3 hemizygous mice, and we found reduced lesions in the Rock2 hemizygous mice. A ROCK2-selective inhibitor, BA-1049 was used to investigate efficacy in reducing CA lesions after oral administration to Ccm1+/- and Ccm3+/- mice that were bred into a mutator background. After assessing the dose range effective to target brain endothelial cells in an ischemic brain model, Ccm1+/- and Ccm3+/- transgenic mice were treated for 3 (Ccm3+/-) or 4 months (Ccm1+/-), concurrently, randomized to receive one of three doses of BA-1049 in drinking water, or placebo. Lesion volumes were assessed by micro-computed tomography. BA-1049 reduced activation of ROCK2 in Ccm3+/-Trp53-/- lesions. Ccm1+/-Msh2-/- (n=68) and Ccm3+/-Trp53-/- (n=71) mice treated with BA-1049 or placebo showed a significant dose-dependent reduction in lesion volume after treatment with BA-1049, and a reduction in hemorrhage (iron deposition) near lesions at all doses. These translational studies show that BA-1049 is a promising therapeutic agent for the treatment of CA, a disease with no current treatment except surgical removal of the brain lesions.

Conservative management of diffuse cavernous haemangioma of the sigmoid and rectum.

Diffuse cavernous haemangioma is a rare disease of the rectum. It usually presents with a history of rectal bleeding in children and young adults. When conservative methods fail to control bleeding, traditionally resection is recommended. A 50-year-old man presented with per rectal bleeding and was diagnosed with diffuse cavernous haemangioma of the sigmoid and rectum extending up to 40 cm in the left colon through endoscopy, magnetic resonance imaging and computed tomography. The diagnosis was confirmed by biopsy. This patient was successful managed conservatively with tranexamic acid as needed, avoiding the need for resection.

RETINAL CAVERNOUS HEMANGIOMA WITH INTRALESIONAL PHLEBOLITHS.

PURPOSE: To report a case of retinal cavernous hemangioma with intralesional phleboliths, simulating retinoblastoma. METHODS: A healthy 5-month-old girl developed left esotropia and was noted to have atraumatic vitreous hemorrhage with underlying partially calcified mass, suspicious for retinoblastoma. RESULTS: On examination, the visual acuity was fix and follow in the right eye and absent fixation in the left eye. Evaluation of the right eye revealed normal findings. The left eye demonstrated healthy anterior segment and dense vitreous hemorrhage with no view of the postequatorial structures, but with hazy view of the flat peripheral retina and a superonasal retinal mass, covered with fresh hemorrhage. Three white intralesional flecks, consistent with calcification, each measuring 300 µm, were visualized. B-scan ultrasonography confirmed the dense mass with several foci of calcification, suspicious for retinoblastoma, despite poor visualization on funduscopy. Prophylactic intravenous chemotherapy was delivered for globe salvage and systemic protection. At 12-month follow-up, the hemorrhage showed resolution, revealing a superonasal dark blue multilobulated mass with saccular aneurysms, measuring 16 mm in diameter, and with 3 phleboliths (intralesional calcification). Fluorescein angiography demonstrated early and midphase hypofluorescence with late-phase filling and with plasma-erythrocyte separation in some larger aneurysms, characteristic of retinal cavernous hemangioma. CONCLUSION: Retinal cavernous hemangioma can be associated with intralesional calcification (phleboliths).

Intralesional injection of triamcinolone acetonide for cavernous hemangiomas: A case report.

RATIONALE: Cavernous hemangiomas referred to as venous malformations (VMs), are not true vascular tumors. The treatment of cavernous hemangiomas is controversial. PATIENT CONCERNS: A five-year-old girl with a cavernous hemangioma on her right buttock had undergone surgery but recurred 1 month after the operation. DIAGNOSES: Cavernous hemangioma was diagnosed on the basis of physical examination, magnetic resonance imaging (MRI) and postoperative pathologic examination. INTERVENTIONS: We treated her with intralesional injection of triamcinolone acetonide (TCA) for 8 times. OUTCOMES: She was cured and had no recurrence during the 3-month follow-up. LESSONS: This prompts that TCA may provide a more effective and safer choice for the treatment of cavernous hemangiomas.

Atorvastatin Treatment of Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial.

BACKGROUND: More than a million Americans harbor a cerebral cavernous angioma (CA), and those who suffer a prior symptomatic hemorrhage have an exceptionally high rebleeding risk. Preclinical studies show that atorvastatin blunts CA lesion development and hemorrhage through inhibiting RhoA kinase (ROCK), suggesting it may confer a therapeutic benefit. OBJECTIVE: To evaluate whether atorvastatin produces a difference compared to placebo in lesional iron deposition as assessed by quantitative susceptibility mapping (QSM) on magnetic resonance imaging in CAs that have demonstrated a symptomatic hemorrhage in the prior year. Secondary aims shall assess effects on vascular permeability, ROCK activity in peripheral leukocytes, signal effects on clinical outcomes, adverse events, and prespecified subgroups. METHODS: The phase I/IIa placebo-controlled, double-blinded, single-site clinical trial aims to enroll 80 subjects randomized 1-1 to atorvastatin (starting dose 80 mg PO daily) or placebo. Dosing shall continue for 24-mo or until reaching a safety endpoint. EXPECTED OUTCOMES: The trial is powered to detect an absolute difference of 20% in the mean percent change in lesional QSM per year (2-tailed, power 0.9, alpha 0.05). A decrease in QSM change would be a signal of potential benefit, and an increase would signal a safety concern with the drug. DISCUSSION: With firm mechanistic rationale, rigorous preclinical discoveries, and biomarker validations, the trial shall explore a proof of concept effect of a widely used repurposed drug in stabilizing CAs after a symptomatic hemorrhage. This will be the first clinical trial of a drug aimed at altering rebleeding in CA.

Recurrent parotid cavernous haemangioma in an adolescent, successfully treated with Propranolol.

INTRODUCTION: Parotid haemangiomas account for the majority of salivary gland tumours in children. This articles highlights the use of medical treatment for the treatment of parotid haemangioma. CASE SUMMARY: A 4 year old male underwent a superficial parotidectomy for a parotid mass that was found to be a a parotid haemangioma on histology. At the age of 14 years he presented again with a parotid mass. He had imaging which aided the diagnosis of a parotid haemangioma being made. He was treated with successfully propranolol over a period of 6 months. DISCUSSION: There are no clear guidelines for treatment of parotid haemangiomas. These lesions can represent a clinical challenge and optimal management is controversial. It was proposed that propranolol be used for treatment in this particular case. This is a non-invasive form of treatment with minimal side effects.

Congenital Calvarial Hemangioma.

OBJECTIVES: The authors describe a case of congenital calvarial hemangioma successfully managed using propranolol therapy. Presenting symptoms, radiological and pathological features, differential diagnosis, and management of this rare congenital mass are described. CASE PRESENTATION: A 2-year-old boy presented with a 1-year history of a growing right parietal skull mass. No obvious etiology was apparent. No focal neurological deficits or associated craniofacial anomalies were identified. Plain film imaging demonstrated focal thickening of the right parietal bone with internal trabeculations in a sunburst appearance. Computed tomography (CT) scan showed bone thickening with coarsening of the bony trabeculae, minor irregularity of the outer table, unaffected inner table, and no evidence of aggressive features. A diagnostic biopsy of the lesion was performed in the operating room. Microscopic examination was consistent with hemangioma. Based on histological and radiological features of the lesion, it was identified as a cavernous hemangioma. Medical treatment utilizing propranolol was initiated for over 3 years with interval reduction in the lesion size. MRI head following treatment with propranolol demonstrated reduction of the mass compared to preoperative imaging. CONCLUSIONS: Although a rare entity, it is important to consider congenital calvarial hemangioma in the differential diagnosis of slow growing skull lesions due to the possibility of complications as a result of the hemangioma's intracranial extension, and the potential for treatment. En bloc resection has classically been described as a treatment for such lesions, although our case demonstrates that medical treatment with propranolol therapy may be appropriate in certain situations.

Therapeutic surprise! Photodynamic therapy for cavernous haemangioma of the disc.

PURPOSE: To report the response of cavernous haemangioma of the disc to PDT. METHODS AND PATIENTS: A 32 years old lady presented to us with complaints of sudden onset of blurry vision in her right eye. What seemed initially as polypoidal choroidal vasculopathy turned out as cavernous haemangioma of the disc after pneumatic displacement of the sub-retinal haeme. She was treated with PDT as she was prone to recurrent haemorrhage from the lesion due to her low platelet count. RESULTS: Complete regression of the cavernous haemangioma was noted as early as the second week itself and remained regressed for 4 months. CONCLUSION: PDT can be safe option for patients presenting with symptomatic cavernous haemangioma of the disc or retina.

Portal hydatid with secondary cavernomatosis.

The hydatid cyst is a parasitic infection included within the category of zoonoses, in which there exists a direct or indirect relation with animals, particularly with dogs. We report a clinical case of a patient who has undergone surgery of hydatid cyst in the right hepatic lobe. Seven years later the patient presents hydatid cyst in portal vein with secondary cavernomatosis, which is a rare complication. There are few cases described in the literature. The symtomatology presented by hydatid cyst is variable and the diagnosis is made by ultrasonography, TC and/or RNM. The treatment of choice is the surgical removal of the cyst, prior to surgery Albendazol must be administered for 1-2 weeks and be maintained for 4 more weeks after surgery.

Efficacy and Safety of 2% Topical Propranolol Cream for the Treatment of Proliferating Infantile Strawberry Hemangiomas.

OBJECTIVE: To evaluate the efficacy and safety of 2% topical propranolol cream in the treatment of proliferating infantile strawberry hemangiomas. METHODS: A total of 40 infants were enrolled; 2% propranolol cream was applied three times daily. In the subsequent monthly visit, dynamic changes in tumor size, texture, and color were recorded. The adverse events (AEs) were observed. Treatment outcomes were scored on a four-point scale. All patients were followed up for 12 mo after treatment. RESULTS: The overall response was graded Scale 1 (poor response) in 2 patients, Scale 2 (moderate response) in 15 patients, Scale 3 (good response) in 17 patients, and Scale 4 (excellent response) in 6 patients. No significant differences were seen in treatment outcomes between female and male patients, among lesion locations/size, or in the age at the start of the treatment. No obvious AEs were reported. CONCLUSIONS: 2% topical propranolol cream is safe and effective for the treatment of proliferating infantile strawberry hemangiomas.

Is systemic infliximab therapy effective for retinal cavernous hemangioma?

A 10-month-old infant with the diagnosis of retinal cavernous hemangioma involving the macula presented with an outward deviation of the right eye that has been noticed by her parents. Examination revealed a clearing vitreous hemorrhage, and grape-like clusters filled with blood in the posterior pole. After 4 cycles of intravenous infliximab over the period of 3 months, no evident change was noted on the size of the cavernous hemangioma. 

Unexpected disappearance of portal cavernoma on long-term anticoagulation.

Idiopathic non-cirrhotic portal hypertension is a rare disease of unknown etiology. Patients with idiopathic non-cirrhotic portal hypertension have an increased risk of developing portal vein thrombosis and this is especially prevalent when HIV is also present. We describe a unique case of a patient with idiopathic non-cirrhotic portal hypertension associated to HIV, who developed acute portal vein thrombosis that despite anticoagulation transformed in portal cavernoma and disappeared completely after five years of follow-up on continuous anticoagulation.

Critical infantile hepatic hemangioma: results of a nationwide survey by the Japanese Infantile Hepatic Hemangioma Study Group.

BACKGROUND: The current survey aimed to describe the clinical features of critical infantile hepatic hemangioma (IHH) and the implications of recent treatments. MATERIALS AND METHODS: A nationwide survey of critical IHH patients treated between 2005 and 2010 was performed in all 117 registered pediatric surgical hospitals in Japan. As a result, 19 patients were identified and reviewed using a statistical analysis. RESULTS: Abdominal distention (47.4%), high-output cardiac failure (47.4%), coagulopathy (42.1%), and respiratory distress (31.6%) were the major symptoms. Three patients died (1 of coagulopathy, 1 of cardiac failure, and 1 of both). An accompanying portovenous shunt was also highlighted. Infantile hepatic hemangioma was totally insensitive to steroid treatment in 3 (23.1%) of the 13 patients, and 9 (47.4%) of the 19 patients required other treatments. Surgical resection and ß-blocker improved the hematologic data, whereas hepatic arterial ligation and embolization seemed to produce a limited effect. Among the dead patients, several hematologic parameters were significantly worse: the thrombocyte count (pretherapeutic: 73,000 vs 300,000/mm(3), dead vs survivor, respectively [P < .03]; posttherapeutic: 66,000 vs 388,700/mm(3) [P < .003]) and the prothrombin time (posttherapeutic, 35.0 vs 12.1 seconds [P < .0001], dead vs survivor, respectively). CONCLUSION: For critical IHH cases with steroid-insensitive hematologic disorders, alternative treatments including ß-blocker therapy, surgery, and liver transplantation should be considered.

[Propranolol in the treatment of infantile hemangioma: clinical effectiveness, risks, and recommendations]. / Propranolol en hemangiomas infantiles: eficacia clínica, riesgos y recomendaciones.

The therapeutic arsenal for hemangiomas in early childhood can now be considered to include oral ß-blockers, mainly propranolol. These drugs are thought to act as vasoconstrictors, regulating angiogenic pathways and inducing apoptosis of vascular endothelial cells. Although infantile hemangioma is not among the approved indications for ß-blockers, many specialized clinics will prescribe propranolol before resorting to corticosteroids. A dosage of 2 mg/kg/d, is usually employed with a dosing interval of 8 hours. Propranolol is safe, causing few side effects, although cases of hypoglycemia, hypotension, diarrhea, reflux, cold hands and feet, bronchospasm, and hyperkalemia have been described. Generally, these adverse effects have not had serious consequences. Prescription in PHACE syndrome is controversial. In all cases, a cardiologist should assess the patient before treatment begins, blood pressure should be monitored, and pediatric follow-up should be scheduled. This review covers our current understanding of the indications, clinical response, and adverse effects of propranolol, a drug has revolutionized our attitude toward infantile hemangioma and the way we approach therapy. Clinical trials under way are also reviewed.