Case Report

A 53-year-old right-handed female presented with a complaint of chronic headaches for over 30 years. The patient described the headaches as intermittent and "pounding," localizing diffusely throughout her head and eyes. The patient described the intensity of these headaches on a self-rated scale from zero to 10 to be 10 out of 10, decreasing to 7 out of 10 after taking acetaminophen with hydrocodone. The headaches would last anywhere from 10 minutes to 2 hours, and were exacerbated by Valsalva maneuvers such as coughing or defecation. The headaches were associated with dizziness, but the patient denied any associated visual changes, photophobia, diplopia, nausea, vomiting, fevers, chills, weight loss, weakness, paresthesias, palpitations, or syncopal episodes.

The patient's past medical history was significant for thyroidectomy and a history of pituitary thyrotroph hyperplasia secondary to hypothyroidism diagnosed 4 years prior to presentation. This pituitary neoplasm resolved after the patient was started on thyroxine replacement therapy. The patient's family history consisted of a mother with asthma, a sister with hypertension, and another sister with systemic lupus erythematosis. The patient was postmenopausal since age 51 and gravida 4 para 4. She denied any spontaneous abortions or stillbirths. The patient's medications included L-thyroxine, naproxen, acetaminophen/hydrocodone, estrogen replacement therapy, calcium supplementation, and multivitamins.

The patient was afebrile with normal vital signs. Her physical exam was significant for obesity (BMI 31.3), the absence of temporal, scalp, or sinus tenderness, normal oropharyngeal exam, no thyromegaly, no nuchal rigidity or menigismus, normal neurologic exam, normal fundoscopic eye exam, no rashes, and no musculoskeletal abnormalities. The patient's initial laboratory examination was unremarkable. Chemistry panels, complete blood counts, thyroid function tests, anti-nuclear antibodies, rheumatoid factor, coagulation studies, erythrocyte sedimentation rate, and fibrinogen were all within normal limits.

MRI of the patient's brain demonstrated abnormal signal intensity just posterior to the corpus callosum with no associated mass effect or enhancement and abnormal meningeal enhancement along the straight sinus. Magnetic resonance venography demonstrated decreased flow signal in the right transverse and sigmoid sinuses consistent with venous thrombosis.

The patient was subsequently admitted to the inpatient medicine ward for observation and anticoagulation. Prior to beginning anticoagulation, a hypercoaguability workup was initiated. Tests for anticardiolipin antibody, lupus anticoagulant, antithrombin deficiency, hyperhomocysteinemia, and Factor V Leiden/activated protein C resistance were negative. The patient had normal protein C levels, but demonstrated a protein S deficiency. The patient was anticoagulated with unfractionated intravenous heparin and oral warfarin. The patient's naproxen and estrogen replacement therapy were discontinued. Throughout the patient's hospital course, her only complaint remained headache, which did not significantly improve despite adequate anticoagulation. The patient remained without neurological complaints or deficits, and was discharged on oral warfarin, subcutaneous enoxaparin, and codeine for pain control. Upon follow-up one month after discharge, the patient's headaches remained, but the associated dizziness had resolved.

Discussion

Cerebral vein thrombosis (CVT) is a rare and diverse entity. Its incidence has been reported to be from 4-70 per million.^1,2 It can affect patients of all ages, ranging from the neonate to the elderly. The timing of its clinical presentation is extremely varied. It can present subacutely (over 2 days to 1 month), acutely (in less than 2 days), or chronically (greater than 1 month). Its actual clinical presentation is also varied. In a review of four studies of patients with CVT, Bousser identified headache to be the most common symptom. Papilledema, intracranial hypertension, focal neurological deficits, seizures, and altered level of consciousness were the other most reported signs and symptoms.³ Patients with CVT can present with any of these clinical findings in isolation or in combination.

With such a variable clinical presentation, the key to diagnosing CVT lies in neuroimaging. Typically, the initial radiological exam is computed tomography (CT), which shows direct signs of CVT in about 30% of cases, indirect evidence of CVT in up to 80% of cases, and can be completely normal in approximately 30% of cases.⁴ Prior to the advent of magnetic resonance imaging, the key diagnostic test was intra-arterial angiography. Now, with the excellent parenchymal resolution of MRI and because of the more invasive nature of intra-arterial angiography, MRI with associated magnetic resonance venography (MRV) is often the test of choice for the diagnosis and follow-up of CVT.³ There is also evidence to suggest that helical CT venography is another powerful tool in the diagnosis of CVT.^4,5

The etiology of CVT can range enormously as well. Any predisposing condition that can cause deep venous thrombosis in the leg can also cause CVT. Infections are a possible etiology, as facial infections, sinusitis, dental abscesses, and otitis media have been associated with CVT. Apart from infectious etiologies, many local factors such as head trauma or intracranial malignancy can predispose to CVT. Generalized thrombophilia is also a major etiology. Pregnancy, oral contraceptive usage, malignancy, vasculitides, and coagulation disorders (including antithrombin III, protein C or S deficiency, activated protein C resistance, and prothrombin G20210A gene mutations) may all contribute to a generalized thrombophilic state which facilitates the generation of a CVT.³

The mortality of patients with CVT ranges from 5%-30%.⁶ Patients with headache and papilledema alone and patients with obstetric etiologies for CVT have the best prognoses.^7,8 Factors that have been associated with a poor prognosis include advanced age, coma, involvement of cerebellar veins, severely raised intracranial pressure, infectious or malignant causes, hemorrhagic infarction, pulmonary embolism, and intractable seizures.^3,8,9 Two studies have looked at the long-term outcome of CVT patients. In one study, 77 patients with CVT were followed for a mean of 6.5 years, and 86% had no evidence of significant neurological sequelae.⁷ The second study followed 59 CVT patients for a mean of 18.5 months and found that 13% had died, and 44% had some evidence of residual handicap or cognitive impairment.¹⁰ In both studies, however, there was no difference found between patients treated with anticoagulation and those treated with placebo.

The treatment of CVT, namely anticoagulation, remains somewhat controversial. In the first randomized trial comparing unfractionated heparin to placebo for CVT treatment, 20 patients were randomized to either heparin or placebo. Eight patients in the heparin group recovered fully while only one in the placebo group recovered fully. In addition, there were no deaths in the heparin group, but three deaths in the placebo group.¹¹ This favorable result could not be duplicated in a subsequent study where no statistically significant difference could be found in the outcome of 60 CVT patients randomized to either low-molecular-weight heparin or placebo.^10,12 These two studies did, however, confirm the safety of heparin, as heparin-treated groups did not demonstrate a greater risk of hemorrhagic complications versus placebo. Definitive evidence for the efficacy of thrombolysis (with urokinase, streptokinase, or recombinant tissue-plas-minogen activator) in the treatment of CVT is also lacking.^6,13 Although no clear benefit has been demonstrated from heparin or thrombolysis, the general strategy for treatment of CVT has been suggested to be anticoagulation with heparin initially, with local thrombolysis reserved for patients who are worsening despite adequate anticoagulation with heparin.^3,6

In summary, CVT, although relatively rare, can have many varied presentations and should be included in the differential diagnosis of unexplained headache. In fact, there may be no evidence of increased intracranial pressure or focal neurological signs, and as demonstrated in our case report, headache may be the only presenting symptom. The etiology of CVT is varied, and the prognosis for CVT patients is generally good. Although no definitive evidence exists to advocate anticoagulation therapy for CVT patients, the current standard of care entails anticoagulation with heparin followed by oral warfarin.