From GWAS to the clinic: risk factors for intracranial aneurysms

Subarachnoid hemorrhage (SAH) from a ruptured intracranial aneurysm is a devastating subset of stroke, occurring in relatively young people (mean age around 50 years) of whom around a third die within the initial weeks after the bleed. Environmental and genetic risk factors both have a role in SAH. A recent genome-wide association study of intracranial aneurysms in Finnish, Dutch and Japanese cohorts totaling 5,891 cases and 14,181 controls identified three new loci strongly associated with intracranial aneurysms on chromosomes 18q11.2 and 10q24.32, and replicated two previously found loci on chromosomes 8q11.23-q12.1 and 9p21.3. However, these five intracranial aneurysm risk loci identified so far explain only up to 5% of the familial risk of intracranial aneurysms, which makes genetic risk prediction tests currently unfeasible for intracranial aneurysms. New approaches, including identification of causal variants, rare variants and copy number variants, such as insertions and deletions, may improve genetic risk prediction for SAH and intracranial aneurysms. This may lead to diagnostic tools for identifying individuals at increased risk for aneurysm formation and rupture of aneurysms. In this way, genetic diagnostic tools will identify the people who will benefit most from screening by imaging studies for aneurysms and those who are most likely to benefit from preventive treatment of incidentally discovered aneurysms

(Cost-)effectiveness of lower extremity nerve decompression surgery in subjects with diabetes:the DeCompression (DECO) trial-study protocol for a randomised controlled trial

Introduction The peripheral nerves of patients with diabetes are often pathologically swollen, which results in entrapment at places of anatomical narrowing. This results in nerve dysfunction. Surgical treatment of compression neuropathies in the lower extremities (lower extremity nerve decompression (LEND)) results in relief of symptoms and gain in peripheral nerve function, which may lead to less sensory loss (short term) and less associated detrimental effects including foot ulceration and amputations, and lower costs (long term). The aim of the DeCompression trial is to evaluate the effectiveness and (cost-)effectiveness of surgical decompression of compressed lower extremity nerves (LEND surgery) compared with patients treated with conventional (non-surgical) care. Methods and analysis A stratified randomised (1 to 1) controlled trial comparing LEND surgery (intervention) with conventional non-surgical care (control strategy) in subjects with diabetes with problems of neuropathy due to compression neuropathies in the lower extremity. Randomisation is stratified for participating hospital (n=11) and gender. Patients and controls have the same follow-up at 1.5, 3, 6, 9, 12, 18, 24 and 48 months. Participants (n=344) will be recruited in 12 months and enrolled in all affiliated hospitals in which they receive both the intervention or conventional non-surgical care and follow-up. Outcome assessors are blinded to group assignment. Primary outcome: disease-specific quality of life (Norfolk Quality of Life Questionnaire-Diabetic Neuropathy). Secondary outcomes: health-related quality of life (EuroQoL 5-dimension 5-level (EQ-5D5L), 36-item Short Form (SF-36)), plantar sensation (Rotterdam Diabetic Foot Test Battery), incidence of ulcerations/amputations, resource use and productivity loss (Medical Cost Questionnaire, Productivity Cost Questionnaire) during follow-up. The incremental cost-effectiveness ratio will be estimated on the basis of the collected empirical data and a cost-utility model. Ethics and dissemination Ethics approval has been granted by the Medical Research Ethics Committee of Utrecht University Medical Center (reference: NL68312.041.19v5, protocol number: 19-335/M). Dissemination of results will be via journal articles and presentations at national and international conferences

Association Between Beta-Blocker or Statin Drug Use and the Risk of Hemorrhage From Cerebral Cavernous Malformations

BACKGROUND: We aimed to determine the association between beta-blocker or statin drug use and the future risk of symptomatic intracranial hemorrhage or persistent/progressive focal neurological deficit from cerebral cavernous malformations (CCM). METHODS: The population-based Scottish Audit of Intracranial Vascular Malformations prospectively identified adults resident in Scotland first diagnosed with CCM during 1999 to 2003 or 2006 to 2010. We compared the association between beta-blocker or statin drug use after first presentation and the occurrence of new intracranial hemorrhage or persistent/progressive focal neurological deficit due to CCM for up to 15 years of prospective follow-up. We confirmed proportional hazards and used survival analysis with multivariable adjustment for age, intracranial hemorrhage at CCM presentation, and brain stem CCM location. RESULTS: Sixty-three (21%) of 300 adults used beta-blockers (27/63 [43%] used propranolol), and 73 (24%) used statin drugs over 3634 person-years of follow-up. At baseline, the only statistically significant imbalances in prespecified potential confounders were age by statin use and intracranial hemorrhage at presentation by beta-blocker use. Beta-blocker use was associated with a lower risk of new intracranial hemorrhage or persistent/progressive focal neurological deficit (adjusted hazard ratio, 0.09 [95% CI, 0.01–0.66]; P=0.018). Statin use was associated with a nonsignificant lower risk of intracranial hemorrhage or persistent/progressive focal neurological deficit (adjusted hazard ratio, 0.37 [95% CI, 0.01–1.07]; P=0.067). CONCLUSIONS: Beta-blocker, but not statin, use was associated with a lower risk of intracranial hemorrhage or persistent/progressive focal neurological deficit in patients with CCM

Magnesium sulfate in aneurysmal subarachnoid hemorrhage: a randomized controlled trial

BACKGROUND AND PURPOSE: Magnesium reverses cerebral vasospasm and reduces infarct volume after experimental subarachnoid hemorrhage (SAH) in rats. We aimed to assess whether magnesium reduces the frequency of delayed cerebral ischemia (DCI) in patients with aneurysmal SAH. METHODS: Patients were randomized within 4 days after SAH. Magnesium sulfate therapy consisted of a continuous intravenous dose of 64 mmol/L per day, to be started within 4 days after SAH and continued until 14 days after occlusion of the aneurysm. The primary outcome DCI (defined as the occurrence of a new hypodense lesion on computed tomography compatible with clinical features of DCI) was analyzed according to the "on-treatment" principle. For the secondary outcome measures "poor outcome" (Rankin >3) and "excellent outcome" (Rankin 0), we used the "intention-to-treat" principle. RESULTS: A total of 283 patients were randomized. Magnesium treatment reduced the risk of DCI by 34% (hazard ratio, 0.66; 95% CI, 0.38 to 1.14). After 3 months, the risk reduction for poor outcome was 23% (risk ratio, 0.77; 95% CI, 0.54 to 1.09). At that time, 18 patients in the treatment group and 6 in the placebo group had an excellent outcome (risk ratio, 3.4; 95% CI, 1.3 to 8.9). CONCLUSIONS: This study suggests that magnesium reduces DCI and subsequent poor outcome, but the results are not yet definitive. A next step should be a phase III trial to confirm the beneficial effect of magnesium therapy, with poor outcome as primary outcom

The natural history of tarsal tunnel syndrome in diabetic subjects

Introduction: Tibial nerve entrapment is highly prevalent in diabetic subjects, resulting in significantly more neuropathic complaints and concomitant sensory disturbances. The study aim was to assess the impact of tarsal tunnel syndrome (TTS) and sensory loss at baseline on incident diabetic foot ulceration (DFU) in diabetic patients, since decompressing the tibial nerve might change the natural history of the disease. Methods: In this study, 113 subjects with TTS (69 bilateral, 23 left-sided and 21 right-sided) participating in the prospective Rotterdam Diabetic Foot Study were compared to 303 diabetic controls without TTS, regarding incident DFU. Kaplan–Meier analysis and Cox’s regression analysis were used to determine the independent hazard of baseline variables for new DFU. Results: The median observation period was 836.5 days (IQR, 459–1077.8). In bilateral TTS, 17.4% (95% CI: 8.4–26.3%) of subjects experienced DFU versus 8.3% (95% CI: 5.1–11.6%) in controls (left or right) during follow-up (p = 0.0036). In left-sided TTS, no subjects versus 6.2% (95% CI: 3.4–9.0%) in controls had DFUs (p = 0.243). Incident ulceration was seen in 14.3% (95% CI: −0.7% to −29.3%) of right-sided TTS subjects versus 4.1% (95% CI: 1.5–6.3%) in controls (p = 0.034). Besides HbA1c, diminished sensation at the hallux independently increased the risk of ulceration, in patients with (HR: 4.692, p = 0.003) and without (HR: 2.307, p = 0.002) prior DFU. Discussion: Elevated sensory thresholds in TTS render diabetic patients at a higher risk for DFU. With effective surgery, TTS is likely to be an amenable factor to potentially prevent diabetic foot disease and thereby reduce amputation risk. Level of evidence: II

Genes influencing coagulation and the risk of aneurysmal subarachnoid hemorrhage, and subsequent complications of secondary cerebral ischemia and rebleeding

We investigated whether genes influencing coagulation are associated with the occurrence of aneurysmal subarachnoid hemorrhage (SAH) and with secondary cerebral ischemia and rebleeding in patients with aneurysmal SAH. Genotyping for factor V Leiden (G1691A), prothrombin G20210A, methylenetetetrahydrofolate reductase (MTHFR) C677T, factor XIII subunit A Val34Leu, Tyr204Phe and Pro564Leu, and factor XIII subunit B His95Arg was performed in 208 patients with aneurysmal SAH and in 925 controls. Secondary cerebral ischemia occurred in 49 (24%) patients and rebleeding in 28 (14%) during their clinical course of 3 months after the aneurysmal SAH. The risk of aneurysmal SAH was assessed as odds ratio (OR) with 95% confidence interval (95% CI). The risk of secondary cerebral ischemia and rebleeding was assessed as hazard ratio (HR) with 95% CI using Cox regression. Carriers of the subunit B His95Arg factor XIII polymorphism had an increased risk of aneurysmal SAH with 23% of the patients homozygous or heterozygous for the variant allele compared to 17% of control subjects (OR 1.5, 95% CI 1.0-2.2). For the remaining genetic variants no effect on the risk of aneurysmal SAH could be demonstrated. A clear relation with the risk of secondary cerebral ischemia and of rebleeding could not be established for any of the genetic variants. We found that aneurysmal SAH patients are more often carriers of the subunit B His95Arg factor XIII polymorphism compared to controls. This suggests that carriers of the subunit B His95Arg factor XIII polymorphism have an increased risk of aneurysmal SAH. Larger studies should confirm our results. As aneurysmal SAH patients who died soon after admission could not be included in the present study, our results only apply to a population of patients who survived the initial hours after the hemorrhage. For the other studied genetic factors involved in coagulation, no association with the occurrence of aneurysmal SAH or with the occurrence of secondary cerebral ischemia or rebleeding after aneurysmal SAH could be demonstrated