Idiopathic intracranial hypertension: associations with thrombophilia and hypofibrinolysis in men

The existence of an association between idiopathic intracranial hypertension (IIH) and coagulation disorders in men was assessed prospectively. Microthrombi, associated with thrombophilia-hypofibrinolysis, occlude arachnoid sinus villi, thus reducing resorption of cerebrospinal fluid, leading to IIH. Ten consecutively referred men with IIH, nine whites, one African American, median age 36 years, were 2 to 1 matched by age and race by healthy male controls. Polymerase chain reaction assays were done for four thrombophilic and one hypofibrinolytic gene mutations: G1691A factor V Leiden, G20210A prothrombin, C677T MTHFR, platelet glycoprotein IIb/IIIa (PL A1/A2), and 4G/5G polymorphism of the plasminogen activator inhibitor (PAI-1) gene promoter. Coagulation measures in plasma included dilute Russel\u27s viper venom time (dRVVT), activated partial thromboplastin time (aPTT), the lupus anticoagulant, factor VIII, factor XI, plasminogen activator inhibitor activity (PAI-Fx), protein C antigenic, protein S total (antigenic), protein S free (antigenic), antithrombin III (functional), and resistance to activated protein C (RAPC). Tests performed on serum included anticardiolipin antibodies, homocysteine, and Lp(a). The body mass index was 40 kg/m(2) or greater (extremely obese) in two men, 30 to 40 kg/m(2) (obese) in three, and was 25 to 30 kg/m(2) in five (overweight). Cases differed from controls for inherited 4G4G homozygosity of the PAI-1 gene, four of 10 (40%) vs. one of 20 (5%), Fisher\u27s p [p(f)]= .031, and for high levels (\u3e21.1 U/mL) of the hypofibrinolytic PAI-1 gene product, PAI-Fx, 5 of 10 (50%) vs. one of 18 (6%), p(f) = .013. Thrombophilic factor VIII was high (\u3e or = 150%) in three of 10 (30%) cases vs. zero of 16 (0%) controls, p(f)=. 046. The thrombophilic lupus anticoagulant was present in two of 10 (20%) cases vs. zero of 32 (0%) controls, p(f) = .052. Heritable hypofibrinolysis and heritable and acquired thrombophilia appear, speculatively, to be treatable etiologies of IIH in men. Understanding contributions of hypofibrinolysis and thrombophilia to the development of IIH should facilitate development of novel new approaches to treat this often-disabling neurologic disorder

Changes in weight, papilledema, headache, visual field, and life status in response to diet and metformin in women with idiopathic intracranial hypertension with and without concurrent polycystic ovary syndrome or hyperinsulinemia

The authors hypothesized that a metformin (MET)-diet would improve symptoms of idiopathic intracranial hypertension (IIH) in women who also had polycystic ovary syndrome (PCOS) or hyperinsulinemia without PCOS. Changes in weight, papilledema, headache, visual fields, and overall life status were prospectively assessed in response to 6 to 14 months on 2.25 g/day MET-diet or diet alone in 36 women with IIH, 23 with PCOS, selected by baseline body mass index (BMI) \u3e or = 25, and no previous surgery for IIH. Overall life status was graded using a self-reported 1-5 scale (1 = well, normal activities; 2 = unwell, usual activities; 3 = poor, usual activities; 4 = poor, no usual activities; 5 = totally disabled). Conventional treatment for IIH was maintained unchanged during MET-diet intervention. The diet was hypocaloric (1500 calories/day), high protein (26% of calories), and low carbohydrate (44%). Of the 23 women with PCOS, 20 received MET-diet and 3 diet only (could not tolerate MET). Of the 13 women without PCOS, 7 were hyperinsulinemic and received MET-diet and 6 received diet alone. The 3 treatment groups (diet only [n = 9], PCOS-MET-diet [n = 20], and hyperinsulinemia-MET-diet [n = 7]) did not differ by median entry BMI (33.3, 37.6, and 35.7 kg/m(2)) or by duration of treatment (10.2, 11.4, and 10.9 months). Median percent weight loss was greatest in the PCOS-MET group (7.7%, P = 0.0015), was 3.3% in the diet only group, and 2.4% (P = 0.04) in the hyperinsulinemia-MET group. Papilledema significantly improved in the diet-alone group from 100% at baseline to 13% (P = 0.03), and in the PCOS-MET group from 95% to 30% (P = 0.002). If headache persisted on therapy, it was less intense-less frequent (P = 0.03) in the diet-only group and in the PCOS-MET group (P = 0.04). As many women with IIH have PCOS, and because weight loss is central to IIH treatment, diet-MET is a novel approach to treat IIH in women with concurrent PCOS or hyperinsulinemia without PCOS

Idiopathic intracranial hypertension, polycystic-ovary syndrome, and thrombophilia

We studied thrombophilia, hypofibrinolysis, and polycystic-ovary syndrome (PCOS) in 65 women consecutively referred because of idiopathic intracranial hypertension (IIH) as a means of better understanding the origin of IIH, with the ultimate goal of developing novel medical therapies for IIH. Our hypothesis: IIH results in part from inadequate drainage of cerebrospinal fluid (CSF) resulting from thrombotic obstruction to CSF resorption-outflow, favored by thrombophilia-hypofibrinolysis. We conducted the polymerase chain reaction (PCR) and assessed serologic coagulation measures in 65 women (64 of them white) with IIH, PCR in 102 healthy white female controls (72 children, 30 age-matched adults), and serologic measures in the 30 adults. Of the 65 patients, 37 (57%) were found to have PCOS; 16 (43%) were obese (BMI \u3e or = 30 to \u3c 40), and 19 (51%) were extremely obese (BMI \u3e or = 40). Of the 65 women with IIH, 25 (38%) were homozygous for the thrombophilic C677T MTHFR mutation, compared with 14% of controls (14/102) ( P = .0002). Thrombophilic high concentrations of factor VIII (\u3e150%) were present in 9 of 65 (14%) IIH cases, compared with 0 of 30 controls (0%) (Fisher\u27s p [p f ] = .053). An increased concentration of lipoprotein A (\u3e or = 35 mg/dL), associated with hypofibrinolysis, was present in 19 of 65 IIH cases (29%), compared with 3 of 30 controls (10%) (p f = .039). IIH occurred in 18 of 65 IIH patients taking estrogen-progestin contraceptives (28%), in 6 patients taking hormone-replacement therapy (9%), and in 5 pregnant subjects (8%). We speculate that PCOS, associated with obesity and extreme obesity, is a treatable promoter of IIH. We also speculate that if thrombophilia-hypofibrinolysis and subsequent thrombosis are associated with reduced CSF resorption in the arachnoid villi of the brain, thrombophilia and hypofibrinolysis-often exacerbated by thrombophilic exogenous estrogens, pregnancy, or the paradoxical hyperestrogenemia of PCOS-are treatable promoters of IIH