Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disease with a wide spectrum of vascular malformations (VMs) involving multiple organs. Nine to 16% of patients with HHT harbor brain arteriovenous malformations (AVMs), which can cause intracranial hemorrhage (ICH). Our objective was to study clinical manifestations of brain AVMs in patients with HHT and correlate these with the specific gene mutated. We reviewed records of 171 patients with HHT and brain AVMs. A history of ICH was found in 27% (41/152) patients, with a mean age of 26 ± 18 range, (0-68) years. All of patients with ICH were neurologically asymptomatic prior to ICH. Multiple brain AVMs were found in 23% (170/39) of patients on initial examination. Genetic test results were available in 109 (64%) patients. Mutations in ENG, ACVRL1, and SMAD4 were present in 75 (69%), 18 (17%), and 2 (2%), respectively. A history of ICH was reported in 24% of patients with an ENG mutation and 27% of patients with an ACVRL1 mutation, with a mean age of 26 ± 16 (range, 2-50) and 18 ± 21 (0-48) years, respectively. No statistically significant differences in age at first brain AVM diagnosis, prevalence of ICH history, age at ICH, or other manifestations of brain AVMs were observed among gene groups. In conclusion, no evidence for differences in brain AVM characteristics was observed among HHT gene groups, although we cannot exclude clinically important differences. Larger studies are needed to further guide brain AVM screening decisions in patients with HHT.

Feasibility of minocycline and doxycycline use as potential vasculostatic therapy for brain vascular malformations: pilot study of adverse events and tolerance.

BACKGROUND: Tetracyclines may be useful in preventing pathological vascular remodeling, thus decreasing the risk of spontaneous hemorrhage from brain vascular malformations. METHODS: Arteriovenous malformation (AVM) and intracranial aneurysm patients undergoing noninvasive management were treated with minocycline or doxycycline (200 mg/day) up to 2 years in a prospective open-label safety pilot trial. The primary outcome was to compare dose-limiting intolerance, defined as treatment-related dose reduction or withdrawal between the agents. RESULTS: Twenty-six patients with AVMs (n = 12) or aneurysms (n = 14) were recruited. Adverse event rates were similar to other reported trials of these agents; 4 of 13 (31%) minocycline and 3 of 13 (23%) doxycycline patients had dose-limiting intolerance (hazard ratio = 3.1, 95% CI = 0.52-18.11, log rank p = 0.70). CONCLUSIONS: It is feasible to propose a long-term trial to assess the potential benefit of tetracycline therapy to decrease hemorrhagic risk in brain vascular malformations.

Estimation of fusiform intracranial aneurysm growth by serial magnetic resonance imaging.

PURPOSE: Intracranial aneurysm (IA) growth is associated with increased morbidity. We sought to establish a quantitative computational method based on contrast-enhanced MR angiography (CE-MRA) for estimating aneurysmal volume changes over time. MATERIALS AND METHODS: Computational volume calculations were tested against a distensible phantom. Untreated patients with IA were followed longitudinally with annual MRI. Maximal linear dimensions along the longitudinal axis and two transverse axes were determined by visual review of maximum intensity projection (MIP) data, and aneurysm volume was approximated as (length x width x height)/2. Averages of the visual approximations were compared to the lumenal volume as determined with a computational algorithm using the MRI data. RESULTS: MRI-based measurements accurately represented volume changes in the phantom (R2 = 0.97, Y = 1.06x + 271 CM3). In the clinical study there were a total of 11 intervals of one-year follow-up in six patients (mean +/- SD, age = 53 +/- 20 years). The raw one-year growth using the computational volume was 9% +/- 17%. The corresponding value for the averaged measurement of the reviewers was 8% +/- 14%. Neither the mean values nor the SDs were different (P = .51). CONCLUSION: MRI-based measurement of aneurysm volume appears feasible for longitudinal studies of aneurysm natural history.

Effect of presenting hemorrhage on outcome after microsurgical resection of brain arteriovenous malformations.

OBJECTIVE: We hypothesized that patients with unruptured arteriovenous malformations (AVMs) at presentation have an increased risk of deterioration compared with patients with ruptured AVMs. METHODS: A consecutive series of 224 patients treated microsurgically by a single neurosurgeon during a period of 6.4 years was analyzed. Initial hemorrhagic presentation was the primary predictor variable. Neurological outcomes were assessed by use of the Modified Rankin Scale (MRS) and Glasgow Outcome Scale (GOS), and logistic regression identified predictors of deterioration at follow-up (mean duration, 1.3 yr) relative to baseline before any intervention. RESULTS: Overall, 120 patients (54%) presented with hemorrhage, and all 224 patients underwent microsurgical resection. Complete resection was achieved in 220 patients (98%). According to GOS score, 13 patients (5.8%) deteriorated; according to MRS score, 45 patients (20.1%) deteriorated. Fifteen patients (6.7%) died. Hemorrhagic presentation was associated with improved outcomes, with a mean change in MRS score of +0.89 in patients with ruptured AVMs and -0.38 in patients with unruptured AVMs (P < 0.001). The final mean MRS scores in patients with unruptured AVMs were better than those in patients with ruptured AVMs (1.44 versus 1.90; P = 0.048). Presentation with an unruptured AVM was a predictor of worsening MRS score (odds ratio, 2.33; 95% confidence interval, 1.3-4.3; P = 0.006) but not of worsening GOS score. CONCLUSION: Presentation with AVM hemorrhage is an underappreciated predictor of outcome after therapy that includes microsurgical resection. Patients with ruptured AVMs tended to have deficits at presentation and generally improved after surgery, whereas patients with unruptured AVMs tended to have normal or nearly normal neurological function at presentation and were susceptible to worsening, albeit slight, as measured by MRS scores. Sensitive outcome measures such as MRS detect subtle symptoms and impairments missed by coarser measures such as GOS. Patients should be counseled that the risks associated with elective resection of unruptured AVMs may be higher than recognized previously. Hemorrhagic brain injury and its secondary effects may mask this surgical morbidity.