Thrombophilia and hypofibrinolysis:
Pathoetiologies of Pseudotumor Cerebri

A free, new (9/12/00) clinical research study at the Jewish Hospital Cholesterol Center, 3200 Burnet Avenue, Cincinnati, OH, 45229. Phone 513-585-7800, Fax 513-585-7950, email glueckch@healthall.com.

Contact us by email or by phone if you are interested in participating.

Purpose: 

Our specific aim is to assess major thrombophilic and hypofibrinolytic pathoetiologies of pseudotumor cerebri ('benign' intracranial hypertension). Our second specific aim is to determine whether treatment of the intracranial hypertension with Diamox will produce symptomatic relief.

We postulate that when exogenous thrombophilic factors (estrogen-containing oral contraceptives, estrogens, corticosteroids) are superimposed on heritable thrombophilic and/or hypofibrinolytic coagulation disorders, multiple ischemic cerebral strokes occur. We postulate that as these strokes resolve, they leave a residual effect of increased intracranial pressure, either by virtue of reduced cerebral clearance of cerebrospinal fluid (CSF), or increased production of CSF, or both. We expect that most patients seen by ophthalmologists with pseudotumor cerebri can be shown to have a coagulation disorder as the pathoetiology, particularly when exogenous estrogens are superimposed on a coagulation disorder.

Significance in Relationship to Human Health:

Recently, it has been realized that sequelae of ischemic stroke, particularly those ischemic strokes mediated by coagulation disorders, may be pseudotumor cerebri (intracranial hypertension).^1-8 The major initial clinical symptom of intracranial hypertension is intractable headache. The longer term optic pathology resulting from intracranial hypertension includes papilledema and progressive loss of visual acuity. ^1-8

We have recently studied two young women who sustained ischemic stroke after thrombophilic oral contraceptives were superimposed on heritable thrombophilia (protein S deficiency, heterozygosity for the prothrombin gene), with subsequent development of intractable headache, and eventual diagnosis of pseudotumor cerebri.⁹

Most cases of pseudotumor cerebri are seen by ophthalmologists, some by neurologists, and some by family physicians/internists. Historically, because pseudotumor cerebri has been considered largely "idiopathic", no concerted effort has been made to assess the interactions of coagulation disorders, exogenous thrombophilic vectors, ischemic stroke, and pseudotumor cerebri. The diagnosis is important for the following reasons:

1. It allows safe, successful treatment of the intracranial hypertension with Diamox.
2. It protects the eyes.
3. It facilitates preventive measures to protect against other venous thrombosis (thrombophlebitis, pulmonary emboli, stroke, etc);

Method of Study:

Patients:

We plan to study 30 new patients seen by ophthalmologists because of pseudotumor cerebri, irrespective of whether they had overt ischemic strokes. Separately, we plan to study 30 new patients with intractable headache after ischemic strokes which occurred while taking oral contraceptives or exogenous estrogen supplementation.

Entry Criteria:

Pseudotumor cerebri diagosed by ophthalmologist or neuro-ophthalmologist, with increased intracranial pressure documented by spinal tap.

Exclusions:

Patients whose ischemic strokes were secondary to embolus (from atrial fibrillation, cardiac myxoma, cholesterol embolus after carotid endarterectomy, bypass surgery, etc) will be excluded as will all patients with hemorrhagic stroke.

Protocol:

Each patient will be seen at the Jewish Hospital Cholesterol Center by Dr Glueck and/or one of the Jewish Hospital resident co-investigators. A detailed medical and gynecological history will be taken along with a history of exogenous oral contraceptives, estrogen replacement therapy, SERM use, or corticosteroids.

A detailed family history will be done, focusing on ischemic stroke, stroke of any type, venous thrombosis, arterial thrombosis, and/or myocardial infarction.

A brief physical examination will be carried out. Measures of height, weight, and blood pressure will be obtained.

Each patient will be examined by Dr Howard Bell or other participating ophthalmologists with a thorough retinal examination and retinal photographs taken to document physical signs of increased intracranial pressure.

Patients judged by Dr. Bell et al to have evidence of increased intracranial pressure will have measures of cerebro-spinal fluid (CSF).

Each participating patient will have the following coagulation measures drawn in the morning in a seated position:

cDNA-PCR:
Factor V Leiden gene, MTHFR gene, Prothrombin Gene, PAI-1 gene, Prothrombin gene, IIb/IIIa polymorphism of the platelet glycoprotein gene.

Serologic tests for thrombophilia:
Protein C, Protein S, Antithrombin III, anticardiolipin antibodies (IgG, IgM), lupus anticoagulant, homocysteine.

Serologic tests for hypofibrinolysis:
Plasminogen activator inhibitor activity (PAI-Fx), lipoprotein (a).

Atherosclerosis risk factors:
Low, very low, and high density lipoprotein cholesterol (LDLC, VLDLC, HDLC).

Intervention:

If intracranial pressure is high by CSF and retinal measures, Diamox 250 mg twice per day will be prescribed. Two months after starting Diamox, repeat retinal examination will be made to document changes in the retina. To obtain semi-quantitative nformation about headache relief on Diamox, the patients will be asked to fill out a daily, self-administered, standardized pain form.

If there are $ 2 major coagulation disorders, discussions with the patients' family doctors will be initiated regarding use of clinical anticoagulant therapy. However, clinical anticoagulant therapy is not part of this research protocol.

Risks and benefits:

Benefits:

Documentation of an underlying heritable coagulation disorder will benefit the patient by either initiating appropriate anticoagulation, by directing family studies of first degree relatives, and by education in avoidance of precipitating environmental factors like estrogens. Documentation of increased intracranial pressure will allow treatment with Diamox, 250 mg BID, designed to reduce intracranial pressure and protect the eye grounds. Knowledge of heritable coagulation disorders should facilitate prevention of thrombotic events in other arterial and venous beds.

Risks:

Documentation of coagulation disorders of a heritable nature, might, were they known to medical insurance companies, be identified as a pre-existing risk for thrombosis. However, the information for the current study will be processed following strict confidentiality rules and will be released only with signed patient consent. After spinal tap to diagnose the level of cerebral spinal fluid pressure, some patients will experience headache, usually not disabling, and usually less than 24 hours.

Payment:

There will be no financial remuneration. Parking will be free in the Alliance ABC garage.

Subject costs:

There are no anticipated costs for the patients. Third party payers have covered diagnostic tests in the past.

References:

1. Sussman J, Leach M, Greaves M, Malia R, Davies-Jones GA. Patentially prothrombotic abnormalities of coagulation in benign intracranial hypertension. J Neurol Neurosurg Psychiatry 1997;62(3):229-33.
2. Green L, Vinker S, Amital H, Amir T, Bar-Dayan Y, Levi Y, Schoenfeld Y. Pseudotumor cerebri in systemic lupus erythematosus. Semin Arthritis Rheum 1995;25(2):103-8.
3. Daif A, Awada A, al-Rajeh S, Abduljabbar M, al Tahan AR, Obeid T, Malibary T. Cerebral venous thrombosis in adults. A study of 40 cases from Saudi Arabia. Stroke 1995;26(7):1193-5.
4. Greer M. Management of benign intracranial hypertension (pseudotumor cerebri). Clin Neurosurg 1968;15:161-74.
5. Backhouse O, Metcalfe T, Goulding P, McEvoy M, Menage M. Factor V Leiden mutation in association with idiopathic intracranial hypertension. Br J Ophthalmol 1998;82(7):844.
6. Konrad D, Kuster H, Hunziker UA. Pseudotumour cerebri after varicella. Eur J Pediatr 1998;157(11):904-6.
7. Singh K, Chye GC. Adverse effects associated with contraceptive implants: incidence, prevention and management. Adv Contracept 1998;14(1):1-13.
8. 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(4):538-42.
9. Glueck CJ, Fontaine RN, Wang P. Interaction of heritable and estrogen-induced thrombophilia: possible pathoetiologies for ischemic optic neuropathy and ischemic stroke. Thrombosis Haemostasis, In Press, 8/23/00.
10. Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith L, Lang JE. Effect of exogenous estrogen on atherothrombotic vascular disease risk related to the presence or absence of the Factor V Leiden mutation (resistance to activated protein C). Am J Cardiology 1999;84:549-554.
11. Balasa VV, Gruppo R, Glueck CJ, Stroop D, Becker A, Pillow A, Wang P. 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. Thrombosis Haemostasis 1999;81: 739-744

 

E-mail: glueckch@healthall.com
or cglueck@fuse.net
Fax: 513-585-7950