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Abstract BACKGROUND: Despite many publications about cerebral cavernous malformations (CCMs), controversy remains regarding diagnostic and management strategies. OBJECTIVE: To develop guidelines for CCM management. METHODS: The Angioma Alliance (www.angioma.org), the patient support group in the United States advocating on behalf of patients and research in CCM, convened a multidisciplinary writing group comprising expert CCM clinicians to help summarize the existing literature related to the clinical care of CCM, focusing on 5 topics: (1) epidemiology and natural history, (2) genetic testing and counseling, (3) diagnostic criteria and radiology standards, (4) neurosurgical considerations, and (5) neurological considerations. The group reviewed literature, rated evidence, developed recommendations, and established consensus, controversies, and knowledge gaps according to a prespecified protocol. RESULTS: Of 1270 publications published between January 1, 1983 and September 31, 2014, we selected 98 based on methodological criteria, and identified 38 additional recent or relevant publications. Topic authors used these publications to summarize current knowledge and arrive at 23 consensus management recommendations, which we rated by class (size of effect) and level (estimate of certainty) according to the American Heart Association/American Stroke Association criteria. No recommendation was level A (because of the absence of randomized controlled trials), 11 (48%) were level B, and 12 (52%) were level C. Recommendations were class I in 8 (35%), class II in 10 (43%), and class III in 5 (22%). CONCLUSION: Current evidence supports recommendations for the management of CCM, but their generally low levels and classes mandate further research to better inform clinical practice and update these recommendations. The complete recommendations document, including the criteria for selecting reference citations, a more detailed justification of the respective recommendations, and a summary of controversies and knowledge gaps, was similarly peer reviewed and is available on line www.angioma.org/CCMGuidelines.

Background Cerebral cavernous malformations (CCMs) are vascular malformations characterized by clusters of enlarged leaky capillaries in the central nervous system. They may result in intracranial haemorrhage, epileptic seizure(s), or focal neurological deficits, and potentially lead to severe disability. Globally, CCMs represent the second most common intracranial vascular malformation in humans, and their familial form (FCCMs) accounts for one-fifth of cases. Neurosurgical excision, and perhaps stereotactic radiosurgery, is the only available therapeutic option. Case reports suggest that propranolol might modify disease progression. Methods Treat_CCM is a prospective, randomized, open-label, blinded endpoint (PROBE), parallel-group trial involving six Italian clinical centres with central reading of brain magnetic resonance imaging (MRI) and adverse events. Patients with symptomatic FCCMs are randomized (2:1 ratio) either to propranolol (40–80 mg twice daily) in addition to standard care or to standard care alone (i.e. anti-epileptic drugs or headache treatments). The primary outcome is intracranial haemorrhage or focal neurological deficit attributable to CCMs. The secondary outcomes are MRI changes over time (i.e. de novo CCM lesions, CCM size and signal characteristics, iron deposition, and vascular leakage as assessed by quantitative susceptibility mapping and dynamic contrast enhanced permeability), disability, health-related quality of life, depression severity, and anxiety (SF-36, BDI-II, State-Trait Anxiety Inventory). Discussion Treat_CCM will evaluate the safety and efficacy of propranolol for CCMs following promising case reports in a randomized controlled trial. The direction of effect on the primary outcome and the consistency of effects on the secondary outcomes (even if none of them yield statistically significant differences) of this external pilot study may lead to a larger sample size in a definitive phase 2 trial. Trial registration ClinicalTrails.gov, NCT03589014 . Retrospectively registered on 17 July 2018.

The presentation and natural history of untreated, symptomatic intramedullary spinal cavernomas at our institution were analyzed. The objective is to provide additional information regarding the natural history of conservatively managed, symptomatic, intramedullary spinal cord cavernous malformations. The medical records of patients treated in our institution between 1989 and 2002 were reviewed to identify those with intramedullary cavernomas. The medical, radiological, surgical, and pathological records from these patients were retrospectively reviewed and analyzed. Fourteen patients were included in the study. The mean age at presentation was 42 years. Four lesions (29%) were located in the cervical region and 10 lesions (71%) were present in the thoracolumbar spinal cord. All patients were symptomatic at the time of presentation. In this cohort of 14 patients, 10 patients (71%) were conservatively managed. For these patients, the mean duration of symptoms before presentation was 10 months. The mean duration of follow-up from the time of presentation was 80 months. The median McCormick grade for conservatively treated patients at presentation was II. During this period, none of the conservatively managed patients had an acute intramedullary bleed. In nine patients, the McCormick grade at the last follow-up evaluation was the same as or better than their score at presentation. Four patients (29%) were treated surgically. The mean duration of symptoms before presentation was 33 months. The mean duration of follow-up from the time of presentation was 42 months. In two surgical patients, the McCormick grade at the last follow-up evaluation remained unchanged compared with their score at presentation, whereas the McCormick grade improved in one patient and deteriorated in another patient. This cohort of conservatively managed patients with symptomatic, intramedullary spinal cord cavernomas was clinically stable throughout the follow-up period. In this series, patients harboring symptomatic spinal cord cavernous malformation did not have significant, permanent neurological decline during the follow-up period when treated with the conservative approach of observation. This data provides additional information for determining the appropriate treatment strategy for patients with intramedullary spinal cavernomas.

From 1983 through 1997, our center diagnosed 130 cases of benign neoplasms: 27 with focal nodular hyperplasia (FNH), 25 with hepatic adenoma, 71 with cavernous hemangioma, and seven with mixed tumors of different diagnoses. Most often these lesions were seen in females [female-to-male ratio (f/m): 5.5/1]. Hepatic adenomas and mixed tumors were seen exclusively in females and FNH predominantly in females (f/m: 26/1). Hemangiomas, however, were not uncommon in men (f/m: 52/19) relative to the other tumors (P < 0.001). Furthermore patients with hemangioma were older (mean age: 49 years) whereas patients with hepatic adenoma, FNH, and mixed tumors were often younger (mean age: 33, 35, and 44 years respectively; P < 0.004). Oral contraceptive steroid use was related by 21 of 25 patients (84%) with hepatic adenoma, 22 of 26 (85%) females with FNH, five of seven (71%) females with mixed tumors, and 10 of 52 (19%) patients with hemangioma. Ninety-five of the 130 patients (73%) had one or more symptoms. There was no statistically significant correlation between symptoms and the size of the lesion, the final diagnosis, and whether there were solitary or multiple masses. Three of 25 (12%) with hepatic adenoma presented with rupture, and one of 27 (4%) with FNH had such a consequence. None of the hemangiomas presented with rupture or progressed to such a state. One patient with hepatic adenoma (4%) had a focus of malignancy. Surgical removal of benign tumors was performed in 82 of 130 patients (63%), and there was one operative mortality (1.2%) in a patient who had a caudate lobe FNH. The types of surgical procedures included segmentectomy (62%), lobectomy (34%), and trisegmentectomy (4%). In two of 84 patients who had undergone laparotomy resection was not technically possible. Resection is recommended in all cases of hepatic adenoma because of fear of rupture or associated focus of malignancy. FNH was not observed to undergo a malignant transformation and will rarely rupture. Surgery is only recommended for symptomatic hemangioma, and size of the lesion is not a criterion for excision.

Intramedullary spinal cord cavernous haemangiomas are rare lesions that can cause severe myelopathic symptoms. The purpose of the present study was to define the pattern of clinical presentation, part of natural history, prognostic factors and therapeutic strategies considering both our own experience and reports from the literature. The data of 48 studies (published between 1903 and 1996), presenting information of all together 107 patients (108 lesions) regarding pre-treatment clinical and radiological factors, treatment strategies, and the outcome, plus our own experience of nine patients were retrospectively re-analyzed. The prognostic influence of pretreatment factors was estimated with the chi-square statistics. Clinical evaluation before/after treatment was performed using the Frankel scale. The average bleeding rate was obtained from the ratio of percentage of first bleeding events in the population to the mean age of the population. There were 47 males and 69 females (aged from twelve to 88 years). Thirty nine percent of the lesions were found in the cervical, 54% in the thoracic (30% upper, 24% lower) and 7% in the lumbar cord. The peak age of presentation was in the fourth decade, the median duration of symptoms was 32 months. Clinical symptoms before treatment were progressive in all cases. Three patterns of clinical presentation could be identified: a) episodes of stepwise clinical deterioration (30%), b) slow progression of neurological decline (41%), c) acute onset with rapid or gradual decline over weeks or months (26%). 58% of the lesions showed clinical or radiological signs of haemorrhage. In 66% of surgical patients (91 efficiently documented cases), clinical improvement was achieved, 28% remained unchanged and 6% deteriorated. Whereas age, sex and lesion location had no influence on the results, duration of symptoms (< three years) correlated significantly to a better outcome (p < 0.02). Surgical management in symptomatic patients is recommended. Once clinical signs caused by the malformation have appeared, the patients tend to experience progressive neurological deterioration.

This is a retrospective study examining the efficacy and safety of Gamma Knife radiosurgery (GKS) in treating patients with cerebral cavernous malformations (CCMs). Between 1993 and 2018, 261 patients with 331 symptomatic CCMs were treated by GKS. The median age was 39.9 years and females were predominant (54%). The median volume of CCMs was 3.1 mL. The median margin dose was 11.9 Gy treat to a median isodose level of 59%. Median clinical and imaging follow-up times were 69 and 61 months, respectively. After the initial hemorrhage that led to CCM diagnosis, 136 hemorrhages occurred in the period prior to GKS (annual incidence = 23.6%). After GKS, 15 symptomatic hemorrhages occurred within the first 2 years of follow-up (annual incidence = 3.22%), and 37 symptomatic hemorrhages occurred after the first 2 years of follow-up (annual incidence = 3.16%). Symptomatic radiation-induced complication was encountered in 8 patients (3.1%). Mortality related to GKS occurred in 1 patient (0.4%). In conclusion, GKS decreased the risk of hemorrhage in CCM patients presenting with symptomatic hemorrhage. GKS is a viable alternative treatment option for patients with surgically-inaccessible CCMs or significant medical comorbidities.

We conducted a retrospective study to determine the incidence and characteristics of submandibular gland hemangioma at our institution. We reviewed the records of all patients who had undergone submandibular gland excision from January 1998 through December 2006. We found a total of 230 such cases. Of these, submandibular gland hemangioma was found in 4 patients (1.7%)–3 women and 1 man, aged 20 to 47 years (mean 34.8). Their duration of symptoms had ranged from 26 to 78 months (mean: 49.3). These symptoms had included submandibular swelling, pain or discomfort, and features of sialadenitis. Computed tomographic angiography had revealed that the hemangiomas were supplied by the facial and lingual arteries. Two of the 4 patients had undergone preoperative vascular embolization, but it had failed to significantly reduce the amount of intraoperative blood loss. Final histopathologic examination had revealed that all 4 lesions were cavernous hemangiomas and that they had replaced the normal glandular structure. No recurrence was seen during a follow-up that ranged from 47 to 72 months (mean: 56.3).

ObjectiveThis study aims to investigate the prevalence of familial cerebral cavernous malformations (FCCMs) in first-degree relatives (FDRs) using familial screening, to describe the distribution of initial symptoms, lesion count on cranial MRI and pathogenic gene in patients.MethodsPatients with multiple CCMs who enrolled from the Treatments and Outcomes of Untreated Cerebral Cavernous Malformations in China database were considered as probands and FDRs were recruited. Cranial MRI was performed to screen the CCMs lesions, and whole-exome sequencing was performed to identify CCM mutations. MRI and genetic screening were combined to diagnose FCCM in FDRs, and the results were presented as prevalence and 95% CIs. The Kaplan-Meier (KM) method was used to calculate the cumulative incidence of FCCM.Results33 (76.74%) of the 43 families (110 FDRs) were identified as FCCM (85 FDRs). Receiver operating characteristic analysis revealed three lesions on T2-weighted imaging (T2WI) were the strong indicator for distinguishing probands with FCCM (sensitivity, 87.10%; specificity, 87.50%). Of the 85 FDRs, 31 were diagnosed with FCCM, resulting in a prevalence of 36.5% (26.2%–46.7%). In families with FCCMs, the mutation rates for CCM1, CCM2 and CCM3 were 45.45%, 21.21% and 9.09%, respectively. Furthermore, 53.13% of patients were asymptomatic, 17.19% were intracranial haemorrhage and 9.38% were epilepsy. The mean age of symptom onset analysed by KM was 46.67 (40.56–52.78) years.ConclusionBased on MRI and genetic analysis, the prevalence of CCMs in the FDRs of families with FCCMs in China was 36.5%. Genetic counselling and MRI screening are recommended for FDRs in patients with more than three CCM lesions on T2WI.

We describe a case of a young male patient with KRIT1-driven familial cavernous malformation syndrome who developed multiple brain cavernomas, intracranial bleeding, and persistent seizures. Due to the relentless growth of cavernous malformations and recurrent intracranial bleeds, it was decided to enrol the patient in the “Propranolol for Intracranial Cavernoma” (PICC) pilot trial at our institution. Over the 5-year treatment period with 20 to 40-mg oral propranolol three times daily (TDS), we noted the near-complete arrest of the growth of cavernous malformations with no further evidence of intracranial bleeding or any further seizures. The observed outcome is consistent with the extremely limited published literature on the topic; thus, this case provides important evidence that supports the use of propranolol as a prophylactic treatment for paediatric intracranial cavernomas. We strongly encourage and recommend future prospective randomised controlled trials to definitively assess and characterize the therapeutic utility of propranolol in this patient population.

Non-traumatic intracranial hemorrhage includes subarachnoid hemorrhage, subdural hemorrhage, and intracerebral hemorrhage (ICH), which can be classified as primary or secondary. Primary ICH is due to arterial hypertension or cerebral amyloid angiopathy, and secondary ICH is due to cerebral vascular malformations, coagulopathies, infectious complications, brain tumors, and illicit stimulant drug use. This review explores the epidemiology and management of non-traumatic ICH in women, with a focus on pregnancy and the post-partum period, defined as 6 weeks post-delivery.