Brief Communication
Evidence for genetic susceptibility to thrombosis in idiopathic intracranial hypertension

https://doi.org/10.1016/j.thromres.2003.09.030Get rights and content

Introduction

Idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri or benign intracranial hypertension, is the diagnostic term used for a syndrome defined by modified Dandy criteria [1]. These are:

  • (1)

    signs and symptoms of increased intracranial pressure,

  • (2)

    absence of localizing findings on neurological examination,

  • (3)

    absence of deformity, displacement, or obstruction of the ventricular system and otherwise normal neurodiagnostic studies, except for increased cerebrospinal fluid pressure,

  • (4)

    awake and alert patient,

  • (5)

    no other cause of increased intracranial pressure present.

Although a clinical picture indistinguishable from IIH may occur because of dural venous thrombosis, the typical MRI from patients with IIH shows no signs of cerebral venous thrombosis. The most widely accepted hypothesis for the cause of raised CSF pressure in IIH is reduced CSF absorption through the arachnoid villi rather than impairment of venous drainage due to cerebral veno-occlusive disease [2], [3], [4], [5], [6], [7]. Although IIH is a disorder of unknown cause, it develops in different settings without an apparent, common pathogenesis. The occurrence of several reports documenting familial clustering suggested that potential genetic polymorphisms may become clinically manifest after exposure to conditions known to precipitate IIH [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22].

A large proportion of patients with IIH have associated conditions such as obesity, pregnancy, oral contraceptive use, SLE, middle ear infection, essential thrombocythemia, polycythemia rubra vera, myeloma, protein C deficiency, antiphospholipid syndrome and Behcet's disease; each can lead to a prothrombotic state [23], [24], [25], [26], [27], [28].

Among the familial thrombophilic states, altered activity of mutated Factor V (FV) is the most common hereditary blood coagulation disorder [29], [30]. FV Leiden (1691G→A substitution) mutation is the most frequently reported abnormality of FV gene associated with increased risk of thrombosis. Four other polymorphisms in the coding sequences of three cleavage sites (FV Hong Kong [1090A→G substitution] and FV Cambridge [1091G→C substitution] in exon 7, a 1628G→A substitution in exon 10 and the R2 allele [4070A→G substitution] in exon 13) are associated with increased risk of thrombosis in different populations [31], [32], [33], [34], [35], [36], [37], [38], [39], [40].

The occurrence of microvascular occlusion of other tissues in addition to the arterial or venous thrombosis in patients with clotting defects has been reported in the literature [41], [42]. This study postulates that IIH patients might have a genetic thrombotic risk factor due to mutated FV that predisposes them to microvascular occlusion in the arachnoid villi that leads to increased intracranial pressure in the presence of other prothrombotic risk factors.

Section snippets

Materials and methods

Fifty-one unrelated patients, diagnosed with IIH at the Hacettepe University School of Medicine, Department of Neurology, Neuro-ophthalmology clinic between 1979 and 2000 were studied. There were 36 female and 15 male patients with a mean±S.D. age, 29.3±11.7 years. Twenty-six patients were evaluated prospectively from May 1997 through December 2000. The remaining 25 patients were identified from previous medical records and agreed to participate in the study. All 51 patients met the modified

Clinical characteristics of IIH patients

Table 1 presents data on the clinical characteristics of the patients. Clinical characteristics of patients with IIH included: obesity in 28 patients, oral contraceptive use or pregnancy in 6 patients, antibiotic use and middle ear infection or sinusitis in 5 patients and vitamin A intake in 2 patients. Six patients also had a diagnosis of Psoriasis, Behcet's disease, thalassemia minor, iron deficiency anemia, portal vein thrombosis or congenital kyphosis. There was a history of affected

Discussion

Our study is the first report of a genetic polymorphism that may be implicated as an underlying prothrombotic susceptibility in IIH. The incidence of FV gene thrombosis-associated polymorphisms is significantly higher in patients with IIH than controls of similar age, sex and demographic distribution (p=0.044, odds ratio: 2.11, 95% confidence interval: 0.97–4.56).

This study also documents an association between acquired risk factors known to precipitate thrombosis such as obesity, oral

Summary

In 51 IIH patients and 68 controls, we scanned three exons (exons 7, 10 and 13) of the FV gene known to be the site of five polymorphisms that are associated with increased thrombosis risk. The prevalence of three FV thrombosis associated polymorphisms (Factor V Leiden, 1628 G→A substitution and R2 allele) in IIH patients was found to be significantly higher compared to the controls (odds ratio 2.1 [95% confidence interval 0.97–4.56], p=0.044). The incidence of associated prothrombotic states

First page preview

First page preview
Click to open first page preview

References (44)

  • F Gjerris et al.

    Intracranial pressure, conductance to cerebrospinal fluid outflow, and cerebral blood flow in patients with benign intracranial hypertension (pseudotumor cerebri)

    Ann. Neurol.

    (1985)
  • J Malm et al.

    CSF hydrodynamics in idiopathic intracranial hypertension: a long-term study

    Neurology

    (1992)
  • A Quattrone et al.

    A hypofibrinolytic state in overweight patients with cerebral venous thrombosis and isolated intracranial hypertension

    J. Neurol.

    (1999)
  • W.A Buchheit et al.

    Papilledema and idiopathic intracranial hypertension: a report of a familial occurrence

    N. Engl. J. Med.

    (1969)
  • J Howe et al.

    Familial benign intracranial hypertension

    Acta. Neurochir. (Wien)

    (1973)
  • A.D Rothner et al.

    Pseudotumor cerebri. Report of a familial occurrence

    Arch. Neurol.

    (1974)
  • D.C Traviesa et al.

    Familial benign intracranial hypertension

    J. Neurol. Neurosurg. Psychiatry

    (1976)
  • I Shapiro et al.

    Familial pseudotumor cerebri and the empty sella syndrome

    Ann. Ophthalmol.

    (1980)
  • C.E Coffey et al.

    Familial benign intracranial hypertension and depression

    Can. J. Neurol. Sci.

    (1982)
  • F Torlai et al.

    Familial pseudotumor cerebri in male heterozygous twins

    Eur. Neurol.

    (1989)
  • I Johnston et al.

    A familial coincidence of pseudotumor cerebri and communicating hydrocephalus

    Neurosurgery

    (1991)
  • C Kharode et al.

    Familial intracranial hypertension: report of a case and review of the literature

    J. Child. Neurol.

    (1992)
  • Cited by (12)

    • Optic Disc Swelling: Papilledema and Other Causes

      2018, Liu, Volpe, and Galetta's Neuro-Ophthalmology: Diagnosis and Management
    • Pediatric Idiopathic Intracranial Hypertension

      2007, Survey of Ophthalmology
      Citation Excerpt :

      Increased intracranial pressure in head trauma may also be the result of cerebral edema.27,188 Hypercoagulable states and dural sinus thromboses have been reported in association with and in some cases are attributed in the mechanism for IIH.37,41,177 For instance, it has been proposed that patients with IIH may have genetic thrombotic risk factors that predispose them to microvascular occlusion in the arachnoid villi.37

    • Idiopathic intracranial hypertension in cystinosis

      2004, Journal of Pediatrics
      Citation Excerpt :

      Elevated homocysteine, an independent risk factor for hypercoagulability, is of particular interest because high levels of total homocysteine have been found in renal transplant recipients with a normal glomerular filtration rate.39,40 In addition, our recent study has shown evidence of a genetic susceptibility to thrombosis by virtue of coagulation Factor V gene polymorphisms in patients with IIH.41 Other studies have reported a possible etiological link between thrombophilia and IIH, postulating that arachnoid villus thromboses interfere with CSF reabsorption and lead to intracranial hypertension.42-44

    View all citing articles on Scopus

    This work was presented at 52nd Annual Meeting of American Society of Human Genetics, Baltimore on October 18th, 2002 as a Poster presentation and published in abstract form.

    View full text