Idiopathic Intracranial Hypertension: Associations with Thrombophilia and Hypofibrinolysis in Men

Abstract

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’s 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/m² or greater (extremely obese) in two men, 30 to 40 kg/m²(obese) in three, and was 25 to 30 kg/m² 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’s p [p_f]= .031, and for high levels (>21.1 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 (≥ 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.

Keywords

Idiopathic intracranial hypertension Thrombophilia Hypofibrinolysis

References

Binder DK , Horton JC , Lawton MT , et al. Idiopathic intracranial hypertension. Neurosurgery 2004;54:538.

Brazis PW , Lee AG . Elevated intracranial pressure and pseudotumor cerebri. Curr Opin Ophthalmol 1998;9:27.

Kesler A , Goldhammer Y , Gadoth N. Do men with pseudo-motor cerebri share the same characteristics as women? A retrospective review of 141 cases. J Neuroophthalmol 2001;21:15.

Bandyopadhyay S. Pseudotumor cerebri. Arch Neurol 2001;58:1699.

Kesler A , Gadoth N. Epidemiology of idiopathic intracranial hypertension in Israel. J Neuroophthalmol 2001;21:12.

Duncan FJ , Corbett JJ , Wall M. The incidence of pseudo-tumor cerebri. Population studies in Iowa and Louisiana. Arch Neurol 1988;45:875.

Kesler A , Gadoth N. Pseudotumor cerebri (PTC—an update). Harefuah 2002;141:297.

Digre KB , Corbett JJ . Pseudotumor cerebri in men. Arch Neurol 1988;45:866.

Kesler A , Fattal-Valevski A. Idiopathic intracranial hypertension in a pediatric population. J Child Neurol 2002;17:745.

10.

Glueck CJ , Iyengar S , Goldenberg N , et al. Idiopathic intracranial hypertension. Associations with coagulation disorders and polycystic-ovary syndrome. J Lab Clin Med 2003;142:35.

11.

Glueck CJ , Goldenberg N , Golnik K , et al. Idiopathic intracranial hypertension: Associations with coagulation disorders and polycystic ovary syndrome. J Invest Med 2004;52(suppl 2):S 382, Abstract.

12.

Glueck CJ , Bell H , Wang P , et al. Idiopathic intracranial hypertension: Associations with coagulation disorders in men. J Invest Med 2004;52(suppl 2):S 349, Abstract.

13.

Sussman J , Leach M , Greaves M , et al. Potentially prothrombotic abnormalities of coagulation in benign intracranial hypertension. J Neurol Neurosurg Psychiatry 1997;62:229.

14.

Daif A , Awada A , al-Rajeh S , et al. Cerebral venous thrombosis in adults. A study of 40 cases from Saudi Arabia. Stroke 1995;26:1193.

15.

Dunkley S , Johnston I. Thrombophilia as a common pre-disposing factor in pseudotumor cerebri. Blood 2004;103:1972.

16.

Munts AG , Vangenderen PJ , Dippel DW , et al. Coagulation disorders in young adults with acute cerebral ischaemia. J Neurol 1998;245:21.

17.

de Bruijn SF , Stam J , Koopman MM , et al. Case-control study of risk of cerebral sinus thrombosis in oral contraceptive users and in carriers of hereditary prothrombotic conditions. The Cerebral Venous Sinus Thrombosis Study Group. BMJ 1998;316:589.

18.

Singh K , Chye GC . Adverse effects associated with contraceptive implants: Incidence, prevention and management. Adv Contracept 1998;14:1.

19.

Wysowski DK , Green L. Serious adverse events in Norplant users reported to the Food and Drug Administration’s MedWatch spontaneous reporting system. Obstet Gynecol 1995;85:538.

20.

Meyer-Heim A , Landau K , Boltshauser E. Treatment of acne with consequences—pseudotumor cerebri due to hypervitaminosis A. Schweiz Rundsch Med Prax 2002;91:23.

21.

Somech R , Arav-Boger R , Assia A , et al. Complications of minocycline therapy for acne vulgaris: Case reports and review of the literature. Pediatr Dermatol 1999;16:469.

22.

Rogers AH , Rogers GL , Bremer DL , et al. Pseudotumor cerebri in children receiving recombinant human growth hormone. Ophthalmology 1999;106:1186.

23.

Green L , Vinker S , Amital H , et al. Pseudotumor cerebri in systemic lupus erythematosus. Semin Arthritis Rheum 1995;25:103.

24.

Sylaja PN , Moosa A , Radhakrishnan K , et al. Differential diagnosis of patients with intracranial sinus venous thrombosis related isolated intracranial hypertension from those with idiopathic intracranial hypertension. J Neurol Sci 2003;215:9.

25.

Balasa VV , Gruppo R , Glueck CJ , et al. The relationship of mutations in the methylenetetrahydrofolate reductase, prothrombin, and plasminogen activator inhibitor-1 genes to plasma levels of homocysteine, prothrombin, and plasminogen activator inhibitor-1 levels in children and adults. Thromb Haemost 1999;81:739.

26.

Glueck CJ , Fontaine RN , Wang P. Interaction of heritable and estrogen-induced thrombophilia: Possible pathoetiologies for ischemic optic neuropathy and ischemic stroke. Thromb Haemost 2001;85:256.

27.

Glueck CJ , Freiberg RA , Fontaine RN , et al. Hypofibrinolysis, thrombophilia, osteonecrosis. Clin Orthop 2002;386:19.

28.

Glueck CJ , Bell H , Vadlamani L , et al. Heritable thrombophilia and hypofibrinolysis. Arch Ophthalmol 1999;117:43.

29.

Brandt JT , Triplett DA , Alving B , et al. Criteria for the diagnosis of lupus anticoagulants: An update. Thromb Haemost 1995;74:1185.

30.

SAS Release 8. 2002. SAS institute, SAS Circle, Box 8000, Cary NC 27512-8000.

31.

Flegal KM , Carroll MD , Ogden CL , et al. Prevalence and trends in obesity among US adults, 1999-2000. JAMA 2002;288:1723.

32.

O’Donnell J , Tuddenham EG , Manning R , et al. High prevalence of elevated factor VIII levels in patients referred for thrombophilia screening: Role of increased synthesis and relationship to the acute phase reaction. Thromb Haemost 1997;77:825.

33.

Glueck CJ , Wang P , Sieve-Smith L , et al. Metformin induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with polycystic ovary syndrome. Metabolism 1999;48:511.

34.

Hoibraaten E , Mowinckel MC , de Ronde H , et al. Hormone replacement therapy and acquired resistance to activated protein C: Results of a randomized, double-blind, placebo-controlled trial. Br J Haematol 2001;115:415.

35.

Hoibraaten E , Qvigstad E , Anderson TO , et al. The effects of hormone replacement therapy (HRT) on hemostatic variables in women with previous venous thromboembolism—results from a randomized, double-blind, clinical trial. Thromb Haemost 2001;85:775.

36.

Glueck CJ , Kupferminc MJ , Fontaine RN , et al. Genetic hypofibrinolysis in complicated pregnancies. Obstet Gynecol 2001;97:44.

37.

Sugerman HJ , DeMaria EJ , Felton WL 3rd , et al. Increased intra-abdominal pressure and cardiac filling pressures in obesity-associated pseudotumor cerebri. Neurology 1997;49:507.

38.

Karahalios DG , Rekate HL , Khayata MH , et al. Elevated intracranial venous pressure as a universal mechanism in pseudotumor cerebri of varying etiologies. Neurology 1996;46:198.

39.

O’Donnell J , Mumford AD , Manning RA , et al. Elevation of FVIII: C in venous thromboembolism is persistent and independent of the acute phase response. Thromb Haemost 2002;83:10.

40.

Kraaijenhagen RA , in’t Anker PS , Koopman MM , et al. High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism. Thromb Haemost 2000;83:5.

41.

O’Donnell J , Laffan M. Elevated plasma factor VIII levels—a novel risk factor for venous thromboembolism. Clin Lab 2001;47:1.

42.

Benilde CL , Michela C , Mirella F , et al. High plasma levels of factor VIII and risk of recurrence of venous thromboembolism. Br J Haematol 2004;124:504.

43.

Kamphuisen PW , Houwing-Duistermaat JJ , van Houwelingen HC , et al. Familial clustering of factor VIII and von Willebrand factor levels. Thromb Haemost 1998;79:323.

44.

Kamphuisen PW , Lensen R , Houwing-Duistermaat JJ , et al. Heritability of elevated factor VIII antigen levels in factor V Leiden families with thrombophilia. Br J Haematol 2000;109:519.

45.

Schambeck CM , Hinney K , Haubitz I , et al. Familial clustering of high factor VIII levels in patients with venous thromboembolism. Arterioscler Thromb Vasc Biol 2001;21:289.

46.

Capucci G , Margaglione M , Ames PR . Comparative prevalence of antiphospholipid antibodies and thrombophilic genotypes in consecutive patients with venous thrombosis. Blood Coagul Fibrinolysis 2001;12:659.

47.

Field SL , Brighton TA , McNeil HP , et al. Recent insights into antiphospholipid antibody-mediated thrombosis. Ballieres Best Pract Res Clin Haematol 1999;12:407.

48.

Meroni PL , Moia M , Derksen RH , et al. Venous thromboembolism in the antiphospholipid syndrome: Management guidelines for secondary prophylaxis. Lupus 2003;12:504.

49.

Juhan-Vague I , Alessi MC , Morange PE . Hypofibrinolysis and increased PAI-1 are linked to atherothrombosis via insulin resistance and obesity. Ann Med 2000;32(suppl 1):78.

50.

Huber K. Plasminogen activator inhibitor type-1 (part one); basic mechanisms, regulation, and role for thromboembolic disease. J Thromb Thromb 2001;11:183.

51.

Tassies D , Espinosa G , Munoz-Rodriguez FJ , et al. The 4G/5G polymorphism of the type 1 plasminogen activator inhibitor gene and thrombosis in patients with antiphospholipid syndrome. Arthri Rheum 2000;43:2349.

52.

Sartori MT , Wiman B , Vettore S , et al. 4G/5G polymorphism of PAI-1 promoter and fibrinolytic capacity in patients with deep vein thrombosis. Thromb Haemost 1998;80:956.

53.

Glueck CJ , Wang P , Bornovali S , et al. Polycystic ovary syndrome, the G1691A factor V Leiden mutation, and plasminogen activator inhibitor activity: Associations with recurrent pregnancy loss. Metabolism 2003;52:1627.

54.

Golnik K , Kardon R , Wall M , et al. Sleep apnea and intracranial hypertension in men. Ophthalmology 2002;109:482.