International multicentre validation of the arteriovenous malformation-related intracerebral haemorrhage (AVICH) score.

OBJECTIVE: The recently published arteriovenous malformation-related intracerebral haemorrhage (AVICH) score showed better outcome prediction for patients with arteriovenous malformation (AVM)-related intracerebral haemorrhage (ICH) than other AVM or ICH scores. Here we present the results of a multicentre, external validation of the AVICH score. METHODS: All participating centres (n=11) provided anonymous data on 325 patients to form the Spetzler-Martin (SM) grade, the supplemented SM (sSM) grade, the ICH score and the AVICH score. Modified Rankin score (mRS) at last follow-up (mean 25.6 months) was dichotomized into favourable (mRS 0-2, n=210) and unfavourable (mRS 3-6;n=115). Univariate and AUROC analyses were performed to validate the AVICH score. RESULTS: Except nidus structure and AVM size, all single parameters forming the SM, sSM, ICH and AVICH score and the scores itself were significantly different between both outcome groups in the univariate analysis. The AVICH score was confirmed to be the highest predictive outcome score with an AUROC of 0.765 compared with 0.705 for the ICH score and 0.682 for the sSM grade. CONCLUSION: The multicentre-validated AVICH score predicts clinical outcome superior to pre-existing scores. We suggest the routine use of this score for future clinical outcome prediction and in clinical research. TRIAL REGISTRATION NUMBER: NCT02920645.

Disruption of a ciliary B9 protein complex causes Meckel syndrome.

Nearly every ciliated organism possesses three B9 domain-containing proteins: MKS1, B9D1, and B9D2. Mutations in human MKS1 cause Meckel syndrome (MKS), a severe ciliopathy characterized by occipital encephalocele, liver ductal plate malformations, polydactyly, and kidney cysts. Mouse mutations in either Mks1 or B9d2 compromise ciliogenesis and result in phenotypes similar to those of MKS. Given the importance of these two B9 proteins to ciliogenesis, we examined the role of the third B9 protein, B9d1. Mice lacking B9d1 displayed polydactyly, kidney cysts, ductal plate malformations, and abnormal patterning of the neural tube, concomitant with compromised ciliogenesis, ciliary protein localization, and Hedgehog (Hh) signal transduction. These data prompted us to screen MKS patients for mutations in B9D1 and B9D2. We identified a homozygous c.301A>C (p.Ser101Arg) B9D2 mutation that segregates with MKS, affects an evolutionarily conserved residue, and is absent from controls. Unlike wild-type B9D2 mRNA, the p.Ser101Arg mutation failed to rescue zebrafish phenotypes induced by the suppression of b9d2. With coimmunoprecipitation and mass spectrometric analyses, we found that Mks1, B9d1, and B9d2 interact physically, but that the p.Ser101Arg mutation abrogates the ability of B9d2 to interact with Mks1, further suggesting that the mutation compromises B9d2 function. Our data indicate that B9d1 is required for normal Hh signaling, ciliogenesis, and ciliary protein localization and that B9d1 and B9d2 are essential components of a B9 protein complex, disruption of which causes MKS.

Aneurysm rebleeding before therapy: a predictable disaster?

OBJECTIVECurrent guidelines for subarachnoid hemorrhage (SAH) include early aneurysm treatment within 72 hours after ictus. However, aneurysm rebleeding remains a crucial complication of SAH. The aim of this study was to identify independent predictors allowing early stratification of SAH patients for rebleeding risk.METHODSAll patients admitted to the authors' institution with ruptured aneurysms during a 14-year period were eligible for this retrospective study. Demographic and radiographic parameters, aneurysm characteristics, medical history, and medications as well as baseline parameters at admission (blood pressure and laboratory parameters) were evaluated in univariate and multivariate analyses. A novel risk score was created using independent risk factors.RESULTSData from 984 cases could be included into the final analysis. Aneurysm rebleeding occurred in 58 cases (5.9%), and in 48 of these cases (82.8%) rerupture occurred within 24 hours after SAH. Of over 30 tested associations, preexisting arterial hypertension (p = 0.02; adjusted odds ratio [aOR] 2.56, 1 score point), aneurysm location at the basilar artery (p = 0.001, aOR 4.5, 2 score points), sac size ≥ 9 mm (p = 0.04, aOR 1.9, 1 score point), presence of intracerebral hemorrhage (p = 0.001, aOR 4.29, 2 score points), and acute hydrocephalus (p < 0.001, aOR 6.27, 3 score points) independently predicted aneurysm rebleeding. A score built upon these parameters (0-9 points) showed a good diagnostic accuracy (p < 0.001, area under the curve 0.780) for rebleeding prediction.CONCLUSIONSCertain patient-, aneurysm-, and SAH-specific parameters can reliably predict aneurysm rerupture. A score developed according to these parameters might help to identify individuals that would profit from immediate aneurysm occlusion.

Solitary Sporadic Cerebral Cavernous Malformations: Risk Factors of First or Recurrent Symptomatic Hemorrhage and Associated Functional Impairment.

OBJECTIVE: To quantify the risk of a first or recurrent hemorrhage and the associated functional impairment in patients with sporadic solitary cerebral cavernous malformations (CCMs) and to investigate the potential risk factors. METHODS: We undertook an observational study (n = 199) of consecutive patients with the diagnosis of a single, sporadic CCM using clinical and magnetic resonance imaging follow-up to identify prospective hemorrhage events and associated functional impairment. We calculated the annual hemorrhage risk rates, calculated cumulative risks, and performed uni- and multivariate analysis to assess outcome predictors. RESULTS: There were 199 adults identified, and 712.5 person years of follow-up were analyzed. Overall annual rates of hemorrhage were 6.03%, 11.95%, and 1.03% in the complete cohort, in those presenting with previous hemorrhage, and in those without, respectively. The 5-year risk of hemorrhage was higher in those presenting with previous hemorrhage than those without (40.9%; 95% confidence interval [CI], 31.78-50.73 vs. 8.6%; 95% CI, 3.97-16.95; P < 0.0001) and in those with a brainstem CCM compared with nonbrainstem CCM (51.6%; 95% CI, 37.61-65.46 vs. 17.1%; 95% CI, 4.55-32.04; P < 0.0001). In the multivariate analysis, previous hemorrhage (odds ratio, 7.18; 95% CI, 1.8-28.11; P = 0.005), age less than 45 years (odds ratio, 2.61; 95% CI, 1.03-6.61; P = 0.042), and brainstem location (odds ratio, 7.44; 95% CI, 2.09-26.50; P = 0.002) increased the risk of hemorrhage. Of the patients, 30% showed a moderate or severe disability associated with a CCM hemorrhage (5-year risk of severe hemorrhage, 8.9%; 95% CI, 5.50-13.99). CONCLUSIONS: This study provides an estimate of symptomatic hemorrhage risk and the associated disability in patients with sporadic solitary CCM and an investigation of risk factors.