A dangerous, easy-to-miss, neurologic emergency
A 32 year-old female presents to the ED with 36 hours of right-sided headache, associated with nausea and vomiting. This is her second visit within the prior 36 hours. Her pain improved with intravenous medications during her first ED visit, and no testing was completed at that time. However, several hours after discharge her headache returned and continued to worsen. She has no past medical history, with no history of headaches, and only takes oral contraceptives. She is mildly tachycardic to 102, though the rest of her vital signs are normal. Her neurologic examination including cranial nerves II through XII, sensory, motor, reflexes, gait, and cerebellar testing is normal. You order an IV and basic medications for headache treatment. What could you be missing in this patient? Is this just another patient needing the standard “headache cocktail”?
Many conditions emergency physicians evaluate are often simple and straightforward. The patient with a headache is one such symptom, as a headache can range from the simple tension headache to deadly intracerebral hemorrhage. We are taught to evaluate for red flags in patients that signify potential risk for morbidity and mortality. Cerebral venous thrombosis (CVT) is one such disorder that can have significant morbidity and mortality.
CVT is a rare disorder, accounting for approximately 1% of strokes, with an annual incidence of 1.32 cases per 100,000 person-years [1–4]. The disease includes thrombosis of the cerebral veins and major dural sinuses. CVT is more common in patients with history of thrombophilia, women on oral contraceptives, or during pregnancy [1–5]. It is three times more common in women.5 The diagnosis is often delayed, approximately 4–7 days after symptoms onset [6–8]. The majority of patients present under the age of 50 years (80%), with a mean age of 39 years [1,2,6]. Less than 10% of patients present over the age of 60 years [3,6].
Due to the variety of signs and symptoms, CVT can be a difficult diagnosis. CVT should be suspected in the table detailing scenarios warranting investigation. The signs and symptoms are highly variable, as can the onset including acute, subacute, or chronic [1–3].
This wide variety of symptoms and signs often accounts for the potential to miss this diagnosis. Of note, a young female on oral contraceptives (OCPs) with a persistent headache is more likely to be experiencing a tension or migraine headache. The emergency physician should closely evaluate for other features concerning for CVT, especially objective neurologic findings, shown in the table.
Symptoms are often associated with the thrombus location, though these are not always classic [3,4]. Cortical vein thrombosis presents with motor and sensory deficits, as well as seizure. Sagittal sinus thrombosis may present with motor deficits, bilateral deficits, and seizures. Patients with thrombus in the lateral sinus may present with intracranial hypertension and headache alone. Thrombosis of the left transverse sinus can present as aphasia, while thrombosis of the deep venous sinus can cause behavioral symptoms due to lesions in the thalamus. Cavernous sinus thrombosis, a different entity, is associated with ocular pain, chemosis, proptosis, and oculomotor palsies [3,4].
Four major syndromes have been described: isolated intracranial hypertension (which is the most common), focal neurologic abnormality, seizure, and encephalopathy. The patient may present with one or multiple syndromes [2–4].
- For intracranial hypertension, the most frequent symptom is a localized, persistent headache, which is seen in up to 90% of patients with acute presentation. This means that 10% of patients will not have a headache during their course, which can delay diagnosis [7–9]! Headache may be sudden in onset and severe, mimicking subarachnoid hemorrhage, or it may be persistent and gradually worsening. The headache is rarely characterized as “worst of life.” It often worsens with valsalva, cough, or bending over due to increased ICP [9,10].
- Focal neurologic deficits are found in 37%–44% of patients, with motor weakness (monoparesis or hemiparesis) the most common focal symptom [7,9]. Fluent aphasia may also be seen, though sensory deficits are not common [1,2].
- Seizures, including focal, generalized, and status epilepticus, are seen in 30–40% of patients [7,11]. As seizures are rare in strokes, CVT should be considered in any patient with a focal neurologic deficit and seizure [1,2].
- The final syndrome is encephalitis, which can be found in patients with thrombosis of the straight sinus or with severe cases including extensive hemorrhage, edema, and large venous infarcts leading to herniation [1,2,4]. Elderly patients more commonly present with altered mental status and confusion as compared to younger patients .
What is the difference between cerebral venous thrombosis and cavernous venous sinus thrombosis? CVT and CVST have common underlying etiologies including thrombosis. However, CVST includes thrombosis in the cavernous sinuses with infection. As discussed previously, ocular signs and symptoms predominate. Treatment requires anticoagulation and antibiotics [1,2,4,6].
Two major pathophysiological mechanisms are associated with CVT, and both ultimately lead to increased intracranial pressure [3,4].
- Increased venular and capillary pressure results from thrombosis, and as local venous pressure rises, cerebral perfusion decreases causing ischemic injury and cytotoxic edema. This may lead to parenchymal hemorrhage if pressures continue to increase [13,14].
- The second mechanism includes decreased CSF absorption. This also leads to increased pressures, cytotoxic and vasogenic edema, and parenchymal hemorrhage [13,14].
At least one risk factor is present in 85% of patients with CVT. However, the disease is often multifactorial with several risk factors present, such as infection in the patient with thrombophilia [3,4,7]. Multiple risk factors are found in 50% of cases [1,15]. Thrombophilia is discovered or present in 34% of patients including defi-ciencies of antithrombin, protein C, protein S, and factor V Leiden mutation. Pregnancy, postpartum state, hormonal contraceptives are frequent risk factors in women. Local infections including osteitis, mastoiditis, sinusitis, and meningitis are associated with disease development. Chronic inflammatory diseases such vasculitis, inflammatory bowel disease, malignancy, nephrotic syndrome, and hematologic disorders such as polycythemia and essential thrombocytosis can contribute. Other risk factors include head trauma, local injury to the cerebral sinuses, or neurosurgical procedures [1,2,4].
Your patient has several risk factors for CVT including her age, persistent headache, and oral contraceptive use. She denies any known blood disorders and has had no recent infections or trauma. As she has never had headaches before, you consider further testing.
Delays in diagnosis are common due to the wide variety of presentations. This disease must be considered in patients under 50 years of age with acute, subacute, or chronic headaches with atypical features such as focal, objective neurologic defjcit(s) (often not fitting a specific anatomical region or with multiple region involvement), seizures, signs of intracranial hypertension, or hemorrhagic infarction present on initial head CT [1–4]. Patients may improve with pain medication; however, if focal deficit or seizure is present, strongly consider further evaluation for CVT. Emergency physicians are masters of considering and evaluating conditions others may miss. This clinical gestalt plays a large role in finding what is amiss in the history, patient risk factors, and examination.
Laboratory examination including complete blood cell count, metabolic panel, and coagulation panel should be obtained. D-dimer is classically touted as being elevated in these patients [4,9,16,17]. One study found a false negative rate of 24%, and it is normal in 40% of patients with isolated headache and no other symptoms . Thus, this test must not be relied upon to rule out the condition [16,17].
Ultimately, imaging is required for diagnosis. Guidelines from the American Heart Association/American Stroke Association (AHA/ASA) recommend imaging of the cerebral venous system for patients with lobar intracerebral hemorrhage of unclear origin or with infarction across multiple arterial territories [4,6]. Imaging should also be obtained in patients with idiopathic intracranial hypertension and headache with atypical features [4,6].
- Head computed tomography (CT) is a common first line test in patients with new headache, focal neurologic symptom, seizure, or altered mental status. Per ACEP clinical policy, any patient with headache and new abnormal neurologic finding(s) (altered mental status, focal neurologic deficit, etc.) warrants emergent head CT (Level B recommendation) . However, this test has poor sensitivity for CVT. It is normal in 30% of cases, with the majority of findings nonspecific if present. One third of cases demonstrate direct signs: dense triangle sign (hyper-density with triangular shape in posterior superior sagittal sinus), empty delta sign (triangular pattern of contrast enhancement surrounding a central area with no enhancement), and the cord sign (curvilinear density over the cerebral cortex) [3,4,6,19–21]. Indirect signs of CVT are more common and include contrast enhancement over the falx and tentorium, dilated venous structures, small ventricles, and parenchymal abnormalities (seen in 80% including hemorrhagic and nonhemorrhagic lesions) [19–21]. Remember, multiple infarctions or infarctions in several arterial distributions warrant consideration of the disease [1–3].
- CT combined with venography is rapid and reliable and can be used in patients with MRI contraindications (pacemaker). This test has an overall sensitivity of 95% and is helpful for patients with subacute or chronic presentations [1–4,6,22]. Contrast reaction, contrast nephropathy, and radiation exposure may limit its use. Due to availability of CT, this is likely the best test in the ED setting.
- MRI with T2 weighted sequence and MR venography can be used to avoid contrast issues. This modality is most sensitive for diagnosis, but it does have the disadvantage in that anatomical variation exists in the intracranial venous system and the time involved [1,3,6,22–28]. MRI findings are dependent on the thrombus age. If the diagnosis is based on lack of blood flow only, the test may be false positive [3,4,22,29]. Contrast is needed with venography, as MRI alone will not identify thrombus and lack of blood flow [1,4,6]. This test is often unavailable in the ED, thus CT with venography is the usual go-to imaging modality.
- If CT and MR imaging modalities do not reveal the diagnosis but the diagnosis is still under consideration, cerebral intra-arterial angiography may be used [3,6,30,31]. This test is best for cortical vein thrombosis [3,4,6].
A lumbar puncture (LP) may be considered to evaluate for meningitis, especially in patients with fever and true neck stiffness. However, results of the LP often reveal nonspecific findings such as increased protein, increased RBCs, and lymphocytosis. These findings may appear similar to viral meningitis. The presence of CVT risk factors, objective neurologic deficits, and deficits in multiple arterial distributions should raise suspicion for CVT. If concern for CVT is present after obtaining LP, imaging should be strongly considered as discussed above. Viral studies including PCR should be ordered if LP is completed [1,2,4,9].
The patient receives a noncontrast head CT, which reveals hyperdensities along the right sigmoid sinus. You speak with the radiologist concerning the need for further imaging, and MRV demonstrates thrombosis of the right transverse and sigmoid sinuses. Now that you have the diagnosis, what is the proper management?
Death can occur in approximately 5% of patients, and this most commonly occurs with supratentorial lesions leading to increased ICP with herniation [1–3,15]. Management focuses on first addressing life-threatening complications including coma, seizures, or increased intracranial pressure (ICP). This is followed by specific therapy, supportive care, and treatment of underlying causes and complications [1–4,6]. Treatment goals are shown above detailing management goals.
For patients with signs concerning for increased ICP (posturing, change in breathing, decreased mental status), immediate action must be taken. Elevation of the head of the bed, mannitol or hypertonic saline, admission to intensive care unit, and ICP monitoring may be required for stabilization [3,4,6,32]. If these are ineffective at initial ICP management, decompressive hemicraniectomy may be needed with neurosurgical consultation [1,2,32–34].
You speak with the patient about the diagnosis. She does not show any signs of decompensation in her current state. However, what treatment and further evaluation does she require?
Consulting the neurology and hematology teams with admission to a stroke unit is recommended, as these patients may decline. Specific therapy includes anticoagulation with heparin initially, followed by transition to warfarin once clinically stable [1–3,6,35]. Anticoagulation recanalizes occluded vasculature, prevents thrombus propagation, and decreases risk of deep venous thrombosis and pulmonary embolism. In the past anticoagulation has been controversial, as rates of intracranial hemorrhage (ICH) approach 50% before treatment [2,35,36]. However, the presence of ICH is not a contraindication for anticoagulation. Literature has demonstrated that no new diagnosis of symptomatic ICH has occurred with anticoagulation therapy, despite the presence of ICH on initial imaging [2–4,35,36]. Thus, anticoagulation is warranted with or without the presence of intracranial hemorrhage on presentation, as anticoagulation is associated with a significant reduction in death [1–6,35]. The duration of treatment is 3–6 months if provoked, versus 6–12 months if unprovoked. 3,6 Use of the new oral anticoagulants has not been studied in this disease [6,35,36]. Thrombolysis, either systemic or catheter-directed, can be done if anticoagulation fails, but this is uncertain due to the risk of hemorrhage. Intravascular thrombolysis is an emerging treatment [1,2,34,37,38]. These treatments will most likely be ICU-based.
Supportive care includes addressing risk factors such as oral contraceptives, treating infection if present, and seizure prophylaxis if the patient experiences a seizure with an associated supratentorial lesion such as edema, hemorrhage, or infarction on imaging. Seizure prophylaxis otherwise is not required [1,2,11,39]. Further testing for underlying etiology is recommended, including thrombophilia [1,2,3,6]. With evaluation for an underlying condition, follow up imaging including CTV or MRV at 3–6 months is required to assess for recanalization of the affected area [1–4,6].
The patient undergoes test for thrombophilia, which reveals factor V Leiden mutation. She is counseled to stop oral contraceptives and placed on warfarin for anticoagulation.
The mortality is 4.3–5.6% during the acute event and hospitalization. This is due to herniation [1–3,6]. The majority, 88%, experience complete recovery or experience only mild deficits.1–4,40 Unfortunately half of patients have ongoing headaches [1,2,10,40]. The recurrence rate is rare at 3% of patients.40,41 Two thirds of patients achieve recanalization of the vasculature with treatment [3,6,42,43]. Markers for worse long-term prognosis include malignancy or infection as the instigating event, associated intracranial hemorrhage, altered mental status on admission (particularly GCS < 9), male gender, age greater than 37 years, and deep venous system involvement [1–3,7,44].
At her six-month follow up visit, the patient undergoes repeat imaging, which reveals complete recanalization of the affected sinus. She has not experienced any further headaches, and her warfarin is discontinued.
PEARLS FOR THE EMERGENCY PHYSICIAN
- CT with venography is a sensitive, available option in the ED for diagnosing CVT in patients with atypical headaches and risk factors.
- Upon diagnosis, anticoagulation with heparin is indicated in the ED, even though some CVT patients may have hemorrhagic transformation.
Scenarios warranting CVT investigation [1–4]
- Headache: in a pregnant female patient, in a young female on OCPs, or one that is atypical and persistent
- Stroke with no typical risk factors or in the setting of seizure
- Intracranial hypertension with no explanation
- Multiple hemorrhagic infarcts, or hemorrhagic infarcts not in a specific arterial distribution
- Objective neurologic symptoms in a patient with risk factors for CVT
Goals of Management [1–4,6]
- Evaluate and stabilize the immediate condition – elevated ICP, seizure, or infection if present
- Anticoagulation for recanalization of venous thrombosis
- Thrombolytic use in selected patients
- Use of antiepileptic agents in patients with seizures and supratentorial lesion
- Treat underlying condition such as infection and address risk factors such as OCP use or thrombophilia
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