a b s t r a c t

Introduction: Cerebral venous thrombosis (CVT) is an uncommon neUrologic emergency associated with signifi- cant morbidity and mortality that can be difficult to differentiate from other conditions. It is important for the emergency clinician to be familiar with this disease as it requires a high index of suspicion, and Early diagnosis and management can lead to improved outcomes.

Objective: This narrative review provides an evidence-based update concerning the presentation, evaluation, and management of CVT for the emergency clinician.

Discussion: CVT is due to thrombosis of the cerebral veins resulting in obstruction of Venous outflow and in- creased intracranial pressure. Early recognition is important but difficult as the clinical presentation can mimic more common disease patterns. The most common patient population affected includes women under the age of 50. Risk factors for CVT include pregnancy, medications (oral contraceptives), inherited thrombophilia, prior venous thromboembolic event, malignancy, recent infection, and neurosurgery. CVT can present in a variety of ways, but the most common symptom is headache, followed by focal neurologic deficit, seizure, and altered mental status. Imaging studies such as computed tomography (CT) venography or magnetic resonance ve- nography should be obtained in patients with concern for CVT, as non-contrast CT will be normal or have non- specific findings in most patients. Treatment includes anticoagulation, treating seizures and elevated ICP aggres- sively, and neurosurgical or interventional radiology consultation in select cases.

Conclusions: CVT can be a challenging diagnosis. Knowledge of the risk factors, patient presentation, evaluation, and management can assist emergency clinicians.

Published by Elsevier Inc.

1. Introduction

Cerebral venous thrombosis (CVT) is an uncommon neurologic emergency that can lead to stroke, seizures, and death. CVT is defined by thrombosis of the intracranial veins and dural sinuses and has an es- timated annual incidence of 0.3-1.5 cases/100,000 person-years, ac- counting for up to 1% of all strokes worldwide [1-3]. The disease is difficult to differentiate from other more common neurologic conditions due to its variED presentations. Delays in diagnosis are associated with higher morbidity, however, prompt recognition, diagnosis, and man- agement can lead to improved outcomes [4]. Thus, it is important for the emergency clinician to be familiar with this disease.

* Corresponding author at: 3841 Roger Brooke Dr, Fort Sam Houston, TX 78234, United States.

E-mail addresses: Anthony.Spadaro@pennmedicine.upenn.edu (A. Spadaro), Kevin.Scott@pennmedicine.upenn.edu (K.R. Scott), brit.long@yahoo.com (B. Long).

1. Methods

This narrative review provides a focused overview of CVT for emer- gency clinicians. The authors searched PubMed for English language ar- ticles from 1990 to November 2020 using the keyword and Medical Subject Heading “cerebral venous thrombosis” for production of this narrative review, restricting results to retrospective and prospective studies, systematic reviews and meta-analyses, narrative reviews, and clinical guidelines. Initial literature search revealed 486 full text articles. Article inclusion was determined by author review and consensus based on clinical relevance to emergency department (ED) evaluation and management. When available, retrospective and prospective studies, systematic reviews/meta-analyses, and clinical guidelines were prefer- entially selected. A total of 57 articles were determined to be of rele- vance to emergency clinicians by author consensus and included in this narrative review. Of the 57 articles included in this review, there were 5 systematic reviews/meta-analyses, 2 guidelines from clinical so- cieties, 7 RCTs, 24 observational studies, and 19 clinical reviews. Authors did not pool data for meta-analysis, as this is a narrative review.

https://doi.org/10.1016/j.ajem.2021.03.040 0735-6757/Published by Elsevier Inc.

1. history and examination“>Discussion
   1. Pathophysiology

The cerebral veins drain the capillary network that supplies the brain

Table 1

Risk factors associated with CVT.

Risk factor Examples

Medications Oral contraceptives, hormone replacement therapy,

glucocorticoids

with blood (Fig. 1). The dural sinuses also drain the cerebrospinal fluid (CSF) via the arachnoid granulations and return the CSF into circulation

through the blood stream [5]. An obstruction within this drainage sys- tem leads to increased venous pressure and reduced capillary perfusion

Inherited Thrombophilia

Acquired Hypercoagulability

Factor V Leiden, prothrombin 20210A, protein C deficiency

Peripartum, malignancies, systemic lupus, Nephrotic syndrome, inflammatory bowel disease, Sickle cell disease

pressure, which can result in ischemia, edema, Elevated intracranial pressure (ICP), and even hemorrhagic infarction [1,5]. Two types of edema result from CVT: vasogenic and cytotoxic edema [6]. vasogenic edema results from the elevated venous pressure that leads to disrup- tion of the blood brain barrier and blood leakage across the interstitial membrane [6,7]. If the venous pressure remains elevated, subsequent ischemia of cerebral tissue disrupts oxygen dependent biochemical pathways and leads to cytotoxic edema [6,7]. Compression of the nerve fibers within the veins is thought to cause headache [5].

• 1. Epidemiology

Several multicenter cohort studies suggest a female predominance to CVT [8-10]. The International Study on Cerebral Venous Thrombosis (ISCVT), published in 2004, reported 74.5% of patients with CVT were women [9]. Additionally, this study found that 78% of patients with CVT were less than 50 years old [9]. A more recent cohort study of CVT among a Norwegian population found an equal prevalence of CVT among the sexes [11].

Approximately 85% of patients with CVT have at least one identifi- able risk factor for thrombosis (Table 1) [12,13]. Oral contraceptive pill (OCP) use, pregnancy/peripartum status, obesity, and hypercoagulabil- ity are several of the most common risk factors, with OCPs increasing the risk of CVT six-fold [12,14]. Other risk factors include Inflammatory conditions such as vasculitis or connective tissue disorders, sickle cell disease, head trauma, nephrotic syndrome, and dehydration [3,14]. Local infections of the head and neck, such as mastoiditis and sinusitis, have been reported to be associated with CVT, present in 8.2% of cases in one study [15]. Another important potential risk factor is recent sur- gery, particularly neurosurgery, which has been associated with up to 2% of CVT cases [9,12]. Malignancy has been reported to be associated with CVT in approximately 5% of cases, although some studies have

Fig. 1. Cerebral Venous Anatomy. Image Courtesy of Wikimedia Commons: https:// commons.wikimedia.org/wiki/File:Major_venous_sinuses_and_their_tributaries.png

Infections Mastoiditis, meningitis, sinusitis

Surgery Craniotomy, indwelling ventricular catheter

Other Obesity

noted that malignancy is a more common cause of CVT in patients over age 55, present in 25% of cases [15,16].

• 1. History and examination

History should focus on the presence of these risk factors and med- ications that increase risk of thrombosis. In a study of risk factors for CVT, smoking, hypertension, and diabetes did not reach statistical sig- nificance, possibly reflecting the younger age of the population most af- fected by CVT [12]. Thus, the emergency clinician should consider CVT in patients with Stroke-like symptoms without traditional stroke risk fac- tors [12]. One study estimated OCP use among 54-71% of female pa- tients with CVT, while another found OCP use in 10-73% of female patients with CVT [2,3,8,12]. Pregnancy and the first 6 weeks post- partum are higher risk periods for the development of CVT. One study estimated an odds ratio (OR) of 17.24 for pregnancy/post-partum pe- riod for CVT (95% confidence interval (CI) 6.83-44.04) [12], and CVT should be considered in patients with headache in this population. OCP use can also be easily missed if a thorough medication review is not performed. Additional risk factors identified for CVT include gluco- corticoid use (OR 18.26; 95% CI 3.25-102.55), antiphospholipid syn-

drome (OR 6.98; 95% CI 2.06-23.6), factor V Leiden (OR 2.51; 95% CI 1.93-3.27), prothrombin 20210A (OR 5.53; 95% CI 3.98-7.69), and pro-

tein C deficiency (OR 10.74; 95% CI 3.07-37.65) [12]. One small study found a higher risk of CVT among patients at high-altitude, although many of these patients already had one hypercoagulable risk factor [17]. Patients present along a clinical spectrum based on the location of the thrombus, severity of ICP elevation, and presence of edema, making Diagnosis difficult. Headache is the most common presenting complaint of CVT, occurring in 81-95% of patients, and focal neurologic deficits, seizures, and altered mental status can be other presenting features of CVT (Table 2) [2,8-11,17,18]. However, over 5% of patients will present without headache [18]. While headache is common in ED patients, sev- eral distinguishing factors may suggest CVT, as well as other diseases (Table 3). Additionally, while neurologic abnormalities are often uti- lized as a trigger for additional evaluation in patients presenting with headache, the VENOST study found that 25% of cases of CVT presented as Isolated headache [8]. Unlike with subarachnoid hemorrhage, the headache in CVT tends to be more subacute, rather than sudden in

Table 2

Clinical presentations suggestive of CVT. Clinical presentation

Headache plus sensory or motor deficit, oculomotor palsy, vision impairment, or

papilledema

Atypical or Severe headache in a patient with risk factor(s) for thrombosis History of headache preceding a seizure, stroke, or altered mental status

Stroke in a young female patient or a patient without atherosclerotic risk factors Acute stroke patient who develops a seizure

Stroke patient with neuroimaging that shows infarcts in multiple vascular territories

Table 3

Differential diagnosis and distinguishing features of CVT.

Disease Distinguishing features

Meningitis The classic triad of headache, fever, and neck stiffness is present in 44% of patients with meningitis [19]. Meningeal signs and symptoms, like neck stiffness, suggest meningitis, while focal neurologic deficits and papilledema should raise suspicion for CVT.

subarachnoid hemorrhage Headache, nausea/vomiting, neurologic deficits, and seizures can be the presenting symptoms of SAH or CVT [19,20]. SAH more

commonly presents abruptly, with the headache reaching maximal intensity within a few minutes of onset, as opposed to headaches associated with CVT that typically develop over the course of days. thunderclap headache is more common in SAH [19]. SAH also tends to occur in a slightly older patient population, with an average age of 57 years [21].

acute angle closure glaucoma Headache, nausea/vomiting, and visual symptoms are common in acute angle closure glaucoma and CVT [19]. Abrupt onset (minutes to hours, rather than days), injected conjunctivae, blurry vision, and decreased pupillary reactivity increase likelihood of acute angle closure glaucoma.

Carotid/vertebral artery dissection Dissection can present as headache with neck pain and focal neurologic deficits. Like CVT, dissection can also present as isolated headache [19]. A history of trauma, neck manipulation, and sudden acceleration-deceleration should raise suspicion for vertebral or carotid dissection. Horner’s syndrome, pulsatile tinnitus, and posterior circulation symptoms such as ataxia should also raise suspicion for dissection [19].

Temporal arteritis Headache and visual symptoms can be the presenting symptoms of temporal arteritis, but additional features such as jaw claudication and fever can help distinguish it from CVT [19]. Additionally, temporal arteritis typically affects an older patient population (over 50 years), compared to patients with CVT (under 50 years) [19,22].

Idiopathic Intracranial Hypertension (IIH)

Headache, cranial nerve palsy, and papilledema can be present in IIH and CVT [ 8,23,24]. Neurologic deficits associated with IIH are more commonly Abducens nerve palsy and visual field defects [23]. Other neurologic deficits in a patient with suspected IIH should also raise suspicion for CVT as the diagnosis. Several small studies found that MRI/MRV in patients with IIH was more likely to have signs of increased ICP on imaging, like flattening of the globe, an empty sella, or optic nerve tortuosity, compared to those with CVT [23,24]. Some studies have suggested that any patient with IIH should have outpatient follow up to determine the need for further evaluation for hypercoagulability [25].

Preeclampsia/Eclampsia Headache, nausea/vomiting, and visual complaints in a pregnant or post-partum patient suggest preeclampsia or CVT [19].

Preeclampsia/eclampsia or HELLP syndrome should be considered in the setting of hypertension or laboratory signs of end organ damage such as proteinuria or Liver function test abnormalities. The presence of focal neurologic deficits should raise suspicion for CVT.

Reversible cerebral vasoconstriction Syndrome (RCVS)

Posterior Reversible Encephalopathy Syndrome

RCVS risk factors include peri-partum state, hypertension, and medications like triptans [8,26]. RCVS is an angiopathy characterized by abnormal vascular tone that leads to vasoconstriction and sometimes seizures and stroke [26,27]. Reoccurring thunderclap headache is characteristic of RVCS and uncommon in CVT [26]. Typical imaging findings include two or more areas of arterial narrowing on MRA [26].

PRES is associated with immunosuppression, end stage renal disease, and hypertension [27,28]. PRES results from endovascular dysfunction and elevated blood flow beyond the cerebral autoregulatory zones resulting in vasogenic edema. Depressed levels of consciousness and headache are more common in PRES. [28] Focal neurologic deficits can occur but are more rare in PRES compared to CVT [28]. Typical MRI findings in PRES are bilateral symmetric partial-occipital lesions [27,28].

Abbreviations: CVT – cerebral venous thrombosis, HELLP – hemolysis, elevated Liver enzymes, low platelets, ICP – intracranial pressure, MRA – magnetic resonance angiography, MRI –

magnetic resonance imaging, MRV – magnetic resonance venogram.

onset [3,8,18]. One study found that 57% of patients presented with sub- acute or Chronic headaches, with symptoms progressing from 4 days to greater than 2 weeks, leaving 43% presenting acutely [8]. Another study reported 60% of patients presented acutely, although this study defined acute as 1-4 days after symptom onset [3]. While rare, there have been case reports of CVT presenting as maximal in onset, “thunderclap” head- aches, which could prove problematic as clinicians may anchor on eval- uating for subarachnoid hemorrhage [3].

Headache that is worsened with maneuvers that increase ICP (i.e., Valsalva maneuver, bending over, etc.) can be suggestive of CVT [3]. However, this is a non-specific finding and is common in other dis- eases that present with headache and increased ICP [3]. The location of headache in CVT is variable given the various locations of the venous si- nuses, although it is controversial if the location of thrombus results in pain over the thrombus site [1]. Headaches can be unilateral, bilateral, frontal, or occipital [1,18]. A study evaluating the clinical features of CVT found that headache plus papilledema or headache plus seizure had a specificity of 97-99% for CVT, but sensitivity was only 7-10% [29]. Unfortunately, no combination of features demonstrated high enough sensitivity to definitively exclude the diagnosis [29]. Headache with a focal neurologic deficit or headache in the setting of recent neu- rologic surgery is also concerning for CVT [12].

Focal neurologic deficits, including cranial nerve palsies and visual field defects, occur in 31-68% of cases of CVT [6,9,17]. Studies have re- ported aphasia and other focal cortical functions, such as Extremity weakness, as presenting symptoms in 13-16% of cases [8,9,11]. Papilledema is found in 28-57% of patients with CVT, and cranial nerve VI palsy may also occur due to elevated ICP [8-10]. Seizures occur in 23-44% of cases, which is markedly higher than in those pa- tients with arterial ischemic stroke, where seizures occur in 2-9% of cases [1,8,9,11,17]. Thus, CVT is an important diagnostic consideration

in patients presenting with seizure and focal neurologic deficit. In se- vere CVT with significant cortical involvement and increased ICP or thrombosis of the deep veins, the patient may present with altered mental status or encephalopathy, which occurs in 17-20% of cases [7]. The location of the thrombus can be associated with Patient symptoms. However, most cases of CVT involve multiple locations and therefore may not present as a clear syndrome [15]. A summary of the frequency of different locations for CVT as well as associated symptoms is pre- sented in Table 4.

• 1. Evaluation
     1. Laboratory testing

Laboratory evaluation cannot be used to rule in or rule out CVT. D- dimer is often elevated in patients with CVT, but literature demonstrates a sensitivity of 82-94% [1-3,18]. The sensitivity is highest in patients with acute, extensive disease and lower in those with subacute or more focal thrombus. A recent prospective multicenter study proposed a predictive Clinical score for the diagnosis of CVT (Table 5) [30]. The score ranges from 0 to 14 points (17 points if D-dimer is utilized). Low risk is 0-2 points, moderate risk is 3-5 points, and high risk is >=6 points. D-dimer is not a mandatory part of the score but can be incorporated (D-dimer >=500 ug/L is 3 points). The authors found that among the 186 patients with low probability for CVT (score 0-2), 11 patients, or 5.9%, were ultimately diagnosed with CVT [30]. Among this group of 11 patients who were low probability but diagnosed with CVT, all had a D-dimer >500 ug/L. [30] In this study the best CVT prediction model resulted from a CVT clinical score >= 6 and D-dimer >=500 ug/L, with a sen- sitivity of 83% and specificity of 86.8% [30]. Although this is a promising step towards development of a useful tool for ruling out CVT, further studies are required [30]. Additionally, due to the poor specificity of D-

Table 4

Frequency and Associated Symptoms of Various Locations of CVT [9,10,15].

Location Frequency (%) Associated symptoms

Superior Sagittal Sinus 62-71 Headache Hemisensory loss Hemiparesis Seizures

Lateral Sinuses 31-47 Headache

Aphasia (left sided) Seizures

Mastoid pain

have been present for less than one week. However, the clot will be- come iso- or hypo attenuated in the subacute and chronic phases [6,33]. Additionally, dehydration and elevated hematocrit may cause a false cord sign [34]. This sign may be found in 6.7-64.6% of cases [33- 36]. Overall, the majority of non-contrast Head CT. in CVT will be normal or have nonspecific signs of increased ICP, parenchymal abnormalities, or infarctions in multiple arterial distributions [2,3,7,18]. Thus, a normal non-contrast head CT should not be used to exclude the diagnosis of CVT, and in patients with severe headache or other findings concerning for CVT, further evaluation is necessary [32]. Hemorrhage may be pres-

Straight Sinus including the Deep Venous system

10-18 Altered Mental Status Gaze palsy

Coma

ent in approximately one third of patients, which is more commonly pa-

renchymal and may occur in several arterial regions [32,34]. Head CT with intravenous (IV) contrast may reveal the “empty delta sign”

Cavernous Sinus 1-4 Eye pain

Proptosis

Cranial nerve III, IV, VI palsy

dimer, this test cannot be used in isolation to rule in CVT [18]. A review by the European Stroke Organization found that D-dimer was more likely to be falsely negative in CVT patients who presented with head- ache alone [16]. They also reported no difference in D-dimer levels in CVT patients with or without focal neurologic deficits [16]. The European Stroke Organization found that thrombophilia screening did not aid in the diagnosis or functional outcome of CVT patients and thus recommend against routine screening in patients suspected of CVT [16].

Lumbar puncture findings are similarly non-specific in CVT and are not definitively indicated for all patients with suspected CVT [7]. In- creased opening pressure, pleocytosis, and increased red blood cells may be present [7]. A study of LP in CVT patients found that LP was nor- mal in 44% of patients with CVT [31]. This study also found that the per- formance of an LP did not affect the prognosis of patients with CVT [31]. However, particularly among acutely ill patients, LP can play an impor- tant role in evaluating for life threatening diagnoses like bacterial men- ingitis or subarachnoid hemorrhage.

• • 1. Imaging

CVT is primarily diagnosed by imaging [13,19,32]. The most com- mon initial imaging modality obtained in the ED in patients with a suspected neurological condition (e.g., high-risk headaches, stroke, in- tracerebral hemorrhage, etc.) is non-contrast head computed tomogra- phy (CT). Non-contrast head CT possesses an important role in evaluating for other dangerous conditions such as intracerebral hemor- rhage. However, this test has poor sensitivity and can be normal in 30-60% of patients with CVT [7,18]. Non-contrast head CT findings concerning for CVT include the “dense triangle sign” (thrombosis in the superior sagittal sinus) and the “cord sign” (thrombosis of cortical or deep veins) [3,7]. The cord sign is an area of increased attenuation in a dural sinus or vein (Fig. 2). This finding represents a clot, which ap- pears hyper-attenuated in the acute phase, typically when symptoms

Table 5

CVT Clinical Score.
Component	Points
Seizure(s) at presentation	4
Known thrombophilia	4
Oral contraception	2
Duration of symptoms >6 days	2
Worst headache ever	1
Focal neurologic deficit at presentation	1

^aD-Dimer >=500 ug/L ^a3

Interpretation: Low risk – 0-2, Moderate risk – 3-5, High risk – greater than 6.

^a D-dimer is not a mandatory part of the score, but if obtained, a D-dimer

>=500 ug/L is 3 points.

(non-opacified thrombus surrounded by the collateral veins of the sinus wall after injection of contrast), which is consistent with a diagno- sis of CVT but is present in only 29-35% of cases [6,34,37]. The empty delta sign may not be present in the acute phase, due to the hyperattenuated thrombus, but it may be present in the subacute phase [6].

CT or magnetic resonance imaging (MRI) with venous pHase imag- ing is the recommended Diagnostic modality and has high sensitivity and specificity. CT venography sensitivity and specificity approximate 95% for diagnosis of CVT and is readily available in most EDs [7,35]. MRI (without venous phase imaging) findings are dependent on the age of thrombus [6,7,38]. In the acute phase, 0-5 days after symptom onset, the thrombus will be predominately isointense on T1 weighted images and hypointense on T2-weighted images, resulting in the poten- tial for missed diagnosis if MRI without venous phase imaging is used [6,34]. In the subacute phase, or days 6-15, the thrombus will be hyper- intense on both T1 and T2 weighted images, thus making diagnosis eas- ier radiographically [6,34]. After 15 days the thrombus can be isointense on T1 and T2 weighted images, again increasing the risk for missed di- agnosis [6,34]. Because the duration of the CVT impacts MRI test charac- teristics, venous phase imaging is necessary. Similar to CT venography, magnetic resonance venography (MRV) displays high sensitivity and specificity for diagnosis [7,35]. While CT venography and MRV likely

Fig. 2. Cord Sign on non-contrast head CT. Image Courtesy of Wikimedia Commons: https://commons.wikimedia.org/wiki/File:Duralvenoussinusthrombosis.png

perform similarly, MRV may be more effective for diagnosis in those with evidence of deep vein involvement (i.e., altered mental status).

• 1. Management

The overall goals of treatment of CVT are to treat the sequelae of CVT, prevent propagation of the clot, recanalize the occluded vessel, and pre- vent thrombosis elsewhere in the body.

• • 1. Seizures

Important sequelae of CVT include seizures and increased ICP. Sei- zure is an independent Prognostic risk factor for mortality [39]. Patients actively seizing should be treated with benzodiazepines. A retrospective study of seizures in CVT reported that lorazepam was the most com- monly used medication to treat acute seizures from CVT [40]. Seizures in CVT are associated with supratentorial lesions [40]. European guidelines make a weak recommendation for patients with CVT who present with seizures and a supratentorial lesion to be started on an anti-epileptic drug to prevent early recurrent seizures, but they make no specific recommendation on agent choice or duration [16]. Seizure prophylaxis for all patients with CVT is not recommended.

• • 1. ICP

Elevated ICP can be a devastating consequence of CVT. A major cause of death from CVT for patients is transtentorial herniation; thus, early management of ICP is critical [39]. There is little evidence to guide treat- ment of increased ICP in the setting of CVT. Therapeutic LP can be con- sidered to reduce ICP, and although no randomized studies have demonstrated therapeutic benefit in CVT, studies have shown that LP is safe in patients with CVT who have isolated intracranial hypertension. LP is contraindicated in those with large lesions at risk for herniation [14,31]. Performing the LP must be balanced with the need for anti- coagulation. European guidelines do not recommend acetazolamide as it has only be evaluated in small non-randomized studies with no clear benefit [16,41]. Steroids have not been shown to be beneficial, with one case-control study showing no difference in rates of death or dependence when compared with control [42]. They may be beneficial in those with an underlying inflammatory disorders such as systemic lupus erythematosus [16]. Although the most recent European Stroke Organization guidelines from 2017 did not comment on these strate- gies, older guidelines from the European Federation of Neurological So- cieties in 2010 recommended elevating the head of bead to 30 degrees, hyperventilation to 30-35 mmHg PaCO₂, and either hypertonic saline or mannitol to lower ICP based on expert opinion [16,43]. Emergent neuro- Surgical consultation is recommended in patients with CVT and signs of impending herniation, as small case series and observational data have shown that Decompressive surgery can be life-saving, but there are little data to guide patient selection [44].

• • 1. Anticoagulation

Anticoagulation is the mainstay of ED treatment of CVT with Low Molecular Weight Heparin or unfractionated heparin (UFH) to recanalize the occluded vein, prevent thrombus propagation, and treat the underlying prothrombotic state [45]. Intracerebral hemor- rhage is not a contraindication to starting anticoagulation. Of the RCTs included in a Cochrane review evaluating anticoagulation for CVT, 25%-49% of patients had intracerebral hemorrhage prior to starting anticoagulation, and no patients developed new intracerebral hemor- rhage (95% CI 0%-9%) [45]. It should be noted that RCTs of anticoagulation in CVT excluded patients with end stage renal disease, liver disease with evidence of synthetic dysfunction, recent gastrointes- tinal bleed, thrombocytopenia, and hypertension with a diastolic pres- sure greater than 110 mmHg [46]. LMWH may be more effective than UFH, unless the patient is clinically unstable or invasive intervention is planned. One RCT of 66 patients found LMWH reduced mortality (0% with LMWH) compared to UFH (19% mortality), as well as increased

likelihood of Complete recovery (88% LMWH versus 63% UFH) [47]. A case-control study found greater independence with LMWH versus UFH (92% versus 84%, OR 2.4) [48]. Warfarin or direct oral anticoagu- lants (DOACs) can be used for long term anticoagulation in CVT [49- 51]. A meta-analysis including 6 studies published in 2020 found DOACs were as effective as warfarin in thrombus recanalization and functional outcomes [52]. Of note, in studies evaluating warfarin or DOACs for patients with CVT, LWMH was the initial anticoagulation agent [52]. Decisions concerning the long-term anticoagulation agent and duration of anticoagulation requires consideration of underlying thrombotic risk factors and should be made in conjunction with a specialist in neurology or hematology. The European guidelines recom- mend a period of 3 to 12 months [16]. The use of systemic thrombolytics has been described, but a systematic review found a risk of serious bleed of 11.5% and a risk of death of 7.7% with systemic thrombolysis. European guidelines currently do not recommend systemic thromboly- sis [16,53]. The role of Endovascular therapy for CVT has previously been complicated by the non-randomized nature of studies on endovascular therapy, with patients in the intervention group more critically ill [41,54]. However, a recent RCT of endovascular therapy showed no difference in mortality or modified Rankin Score (mRS) of 0-1 when compared with standard of care [55]. In this study, over 80% of patients in both groups had a mRS of 0-2 at discharge, considered a good out- come in most of the ischemic stroke literature, reflecting the overall good prognosis for the disease. However, a subset of patients with CVT may benefit from endovascular therapy, and thus the decision to in- tervene should be made in conjunction with neurology, neurosurgery, and interventional radiology if endovascular therapy is available [55]. Although overall the prognosis for CVT is favorable, there are poten- tially devastating consequences to this disease [56]. Clinically stable patients should be admitted for initiation of anticoagulation and neurology and hematology consultation. Patients with evidence of Neurologic deterioration or those requiring neurosurgical or interven- tional radiology procedures should be admitted to an intensive care setting.

• 1. Prognosis

Patients with diagnosed CVT should be admitted for further evalua- tion of the Underlying etiology. Mortality approximates 5%, with risk of permanent disability reaching 20%. The most important factors associ- ated with poor prognosis include malignancy (OR 4.53), coma (OR 4.19), thrombosis of the deep venous system (OR 3.03), any mental sta- tus disturbance (OR 2.18), male gender (OR 1.60), and intracerebral hemorrhage (OR 1.42). In the absence of these factors, prognosis is fa- vorable [16,57].

1. Conclusions

CVT is an uncommon cause of headache and stroke that primar- ily occurs in patients less than 50 years. Women are more com- monly affected than men. Thrombus within the cerebral veins can cause increased ICP, cerebral edema, and ischemia. Patients may ex- perience seizures, stroke, and altered mental status, leading to her- niation and death. Early recognition is important but difficult as the clinical presentation can mimic more common disease patterns. Im- aging studies such as CT venography or MRV should be obtained. Laboratory tests are unlikely to assist in these patients, though D-dimer has been investigated. Treatment includes anticoagulation. Seizures should be treated aggressively. Evidence of herniation re- quires emergent stabilization with lowering of ICP and emergent neurosurgical consultation.

Declaration of Competing Interest

No conflicts for any author.

Acknowledgements

AT, BL, KRS, and AK conceived the idea for this manuscript and contrib- uted substantially to the writing and editing of the review. This manuscript did not utilize any grants or funding, and it has not been presented in ab- stract form. This clinical review has not been published, it is not under con- sideration for publication elsewhere, its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out, and that, if accepted, it will not be published else- where in the same form, in English or in any other language, including elec- tronically without the written consent of the copyright-holder. This review does not reflect the views or opinions of the U.S. government, Department of Defense, U.S. Army, U.S. Air Force, or SAUSHEC EM Residency Program.

References

1. Kristoffersen ES, Harper CE, Vetvik KG, Faiz KW. Cerebral venous thrombosis – epi- demiology, diagnosis and treatment. Cerebral venetrombose – forekomst, diagnostikk og behandling. Tidsskr Nor Laegeforen. 2018;138(12). https://doi.org/ 10.4045/tidsskr.17.1047.
2. Ferro J. Aguiar de Sousa D. cerebral venous thrombosis: an update. Curr Neurol Neurosci Rep. 2019;19(10):1-9.
3. Mehta A, Danesh J, Kuruvilla D. Cerebral venous thrombosis headache. Curr Pain Headache Rep. 2019;23(7):1-6.
4. Ferro JM, Canhao P, Stam J, Bousser MG, Barinagarrementeria F, Massaro A, et al. Delay in the diagnosis of cerebral vein and dural sinus thrombosis: influence on out- come. Stroke. 2009 Sep;40(9):3133-8.
5. Hufnagle JJ, Tadi P. Neuroanatomy, Brain Veins. [Updated 2020 Jan 12]. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan Available from https://www.ncbi.nlm.nih.gov/books/NBK546605/.
6. Canedo-Antelo M, Baleato-Gonzalez S, Mosqueira AJ, Casas-Martinez J, Oleaga L, Vilanova JC, et al. Radiologic clues to cerebral venous thrombosis. Radiographics. 2019 Oct;39(6):1611-28.
7. Mehndiratta MM, Garg S, Gurnani M. Cerebral venous thrombosis-clinical presenta- tions. J Pak Med Assoc. 2006;56(11):513.
8. MD Duman T, MD Uluduz D, MD Midi I, et al. A multicenter study of 1144 patients with cerebral venous thrombosis: the VENOST study. J Stroke Cerebrovasc Dis. 2017;26(8):1848-57.
9. Ferro JM, Canhao P, Stam J, Bousser MG, Barinagarrementeria F, ISCVT Investigators. Prog- nosis of cerebral vein and dural sinus thrombosis: results of the international study on ce- rebral vein and Dural sinus thrombosis (ISCVT). Stroke. 2004 Mar;35(3):664-70.
10. Khealani BA, Wasay M, Saadah M, Sultana E, Mustafa S, Khan FS, et al. Cerebral ve- nous thrombosis: a descriptive multicenter study of patients in Pakistan and Middle East. Stroke. 2008 Oct;39(10):2707-11.
11. Harper CE, Vetvik KG, Zarnovicky S, Hansen JM, Faiz KW. Incidence and Mortality of Ce- rebral Venous Thrombosis in a Norwegian Population. Stroke. 2020 Oct;51(10):3023-9. https://doi.org/10.1161/STROKEAHA.120.030800 PMID:32883194, Epub 2020 Sep 4.
12. Green M, Styles T, Russell T, et al. Non-genetic and genetic risk factors for adult ce- rebral venous thrombosis. Thromb Res. 2018;169:15-22.
13. Zimny A, Dziadkowiak E, Bladowska J, et al. Cerebral venous thrombosis as a diag- nostic challenge: clinical and radiological correlation based on the retrospective analysis of own cases. Adv Clin Exp Med. 2017;26(7):1113-22.
14. Capecchi M, Abbattista M, Martinelli I. cerebral venous sinus thrombosis. J Thromb Haemost. 2018;16(10):1918-31.
15. Ulivi L, Squitieri M, Cohen H, Cowley P, Werring DJ. Cerebral venous thrombosis: a practical guide. Pract Neurol. 2020 Oct;20(5):356-67. https://doi.org/10.1136/ practneurol-2019-002415 PMID:32958591.
16. Ferro JM, Bousser MG, Canhao P, et al. European stroke organization guideline for the diagnosis and treatment of cerebral venous thrombosis – endorsed by the European academy of neurology. Eur Stroke J. 2017;2(3):195-221.
17. Zavanone C, Panebianco M, Yger M, Borden A, Restivo D, Angelini C, et al. Cerebral venous thrombosis at High altitude: a systematic review. Rev Neurol (Paris). 2017 Apr;173(4):189-93.
18. Long B, Koyfman A, Runyon MS. Cerebral venous thrombosis: a challenging neuro- logic diagnosis. Emerg Med Clin North Am. 2017 Nov;35(4):869-78.
19. Tabatabai RR, Swadron SP. Headache in the emergency department: avoiding misdi- agnosis of dangerous secondary causes. Emerg Med Clin North Am. 2016;34(4): 695-716.
20. Do T, Remmers A, Schytz H, et al. Red and orange flags for secondary headaches in clinical practice: SNNOOP10 list. Neurology. 2018;92(3):134-44.
21. Bian L, Liu Y, Nichols LT, et al. Epidemiology of subarachnoid hemorrhage, patterns of management, and outcomes in China: a hospital-based multicenter prospective study. CNS Neurosci Ther. 2012;18(11):895-902.
22. Coutinho JM, Zuurbier SM, Stam J. Declining mortality in cerebral venous thrombo- sis: a systematic review. Stroke. 2014;45(5):1338-41.
23. Ridha MA, Saindane AM, Bruce BB, et al. MRI findings of elevated intracranial pres- sure in cerebral venous thrombosis versus idiopathic intracranial hypertension with transverse sinus stenosis. Neuroophthalmology. 2013;37(1):1-6.
24. Onder H, Kisbet T. Neuroimaging findings in patients with idiopathic intracranial hy- pertension and cerebral venous thrombosis, and their association with clinical fea- tures. Neurol Res. 2020;42(2):141-7.
25. Turay S, Kabakus N, Hanci F, Tunclar A, Hizal M. Cause or consequence: the relation- ship between cerebral venous thrombosis and idiopathic intracranial hypertension. Neurologist. 2019 Sep;24(5):155-60.
26. Ducros A, Wolff V. The typical thunderclap headache of reversible cerebral vasocon- striction syndrome and its various triggers. Headache. 2016 Apr;56(4):657-73.
27. Pilato F, Distefano M, Calandrelli R. Posterior reversible encephalopathy syndrome and Reversible cerebral vasoconstriction syndrome: clinical and radiological consid- erations. Front Neurol. 2020;11:34.
28. Fischer M, Schmutzhard E. Posterior reversible encephalopathy syndrome. J Neurol. 2017;264(8):1608-16.
29. Tanislav C, Siekmann R, Sieweke N, et al. Cerebral vein thrombosis: clinical manifes- tation and diagnosis. BMC Neurol. 2011;11(1):69.
30. Heldner MR, Zuurbier SM, Li B, et al. Prediction of cerebral venous thrombosis with a new clinical score and D-dimer levels. Neurology. 2020;95(7):e898-909.
31. Canhao P, Abreu LF, Ferro JM, et al. Safety of lumbar puncture in patients with cere- bral venous thrombosis. Eur J Neurol. 2013;20(7):1075-80.
32. Dmytriw AA, Song JSA, Yu E, Poon CS. Cerebral venous thrombosis: state of the art diagnosis and management. Neuroradiology. 2018 Jul;60(7):669-85.
33. Vijay RK. The cord sign. Radiology. 2006;240(1):299-300.
34. Leach JL, Fortuna RB, Jones BV, Gaskill-Shipley MF. Imaging of cerebral venous thrombosis: current techniques, spectrum of findings, and diagnostic pitfalls. Radio- graphics. 2006 Oct;26(Suppl. 1):S19-41 discussion S42-3.
35. Khandelwal N, Agarwal A, Kochhar R, Bapuraj JR, Singh P, Prabhakar S, et al. Compar- ison of CT venography with MR venography in cerebral sinovenous thrombosis. AJR Am J Roentgenol. 2006 Dec;187(6):1637-43.
36. Linn J, Pfefferkorn T, Ivanicova K, et al. noncontrast CT in deep cerebral venous thrombosis and sinus thrombosis: comparison of its diagnostic value for both enti- ties. AJNR Am J Neuroradiol. 2009;30(4):728-35.
37. Lee EJ. The empty delta sign. Radiology. 2002;224(3):788-9.
38. Teasdale E. Cerebral venous thrombosis: making the most of imaging. J R Soc Med. 2000;93(5):234-7.
39. Canhao P, Ferro JM, Lindgren AG, Bousser MG, Stam J. Barinagarrementeria F; ISCVT investigators. Causes and predictors of death in cerebral venous thrombosis. Stroke. 2005 Aug;36(8):1720-5.
40. Kalita J, Chandra S, Misra UK. Significance of seizure in cerebral venous sinus throm- bosis. Seizure. 2012 Oct;21(8):639-42.
41. Siddiqui FM, Banerjee C, Zuurbier SM, et al. Mechanical thrombectomy versus intrasinus thrombolysis for cerebral venous sinus thrombosis: a non-randomized comparison. Interv Neuroradiol. 2014;20:336-44.
42. Canhao P, Cortesao A, Cabral M, Ferro JM, Stam J, Bousser MG. Barinagarrementeria F; ISCVT investigators. Are steroids useful to treat cerebral venous thrombosis? Stroke. 2008 Jan;39(1):105-10.
43. Einhaupl K, Stam J, Bousser MG, et al. EFNS guideline on the treatment of cerebral venous and sinus thrombosis in adult patients. Eur J Neurol. 2010;17(10):1229-35.
44. Theaudin M, Crassard I, Bresson D, Saliou G, Favrole P, Vahedi K, et al. Should decom- pressive surgery be performed in malignant cerebral venous thrombosis: a series of 12 patients. Stroke. 2010 Apr;41(4):727-31.
45. Coutinho J, de Bruijn SF, Deveber G, Stam J. Anticoagulation for cerebral venous sinus thrombosis. Cochrane Database Syst Rev. 2011 Aug 10;2011(8):CD002005.
46. de Bruijn SF, Stam J. Randomized, placebo-controlled trial of anticoagulant treat- ment with low-molecular-weight heparin for cerebral sinus thrombosis. Stroke. 1999;30(3):484-8.
47. Misra UK, Kalita J, Chandra S, Kumar B, Bansal V. Low molecular weight heparin ver- sus unfractionated heparin in cerebral venous sinus thrombosis: a randomized con- trolled trial. Eur J Neurol. 2012 Jul;19(7):1030-6.
48. Coutinho JM, Ferro JM, Canhao P, ISCVT Investigators, et al. Unfractionated or low- molecular weight heparin for the treatment of cerebral venous thrombosis. Stroke. 2010 Nov;41(11):2575-80.
49. Ferro JM, Coutinho JM, Dentali F, et al. Safety and efficacy of dabigatran etexilate vs dose-adjusted warfarin in patients with cerebral venous thrombosis: a randomized clinical trial. JAMA Neurol. 2019;76(12):1457-65.
50. Geisbusch C, Richter D, Herweh C, Ringleb PA, Nagel S. Novel factor xa inhibitor for the treatment of cerebral venous and sinus thrombosis: first experience in 7 pa- tients. Stroke. 2014 Aug;45(8):2469-71.
51. Mendonca MD, Barbosa R, Cruz-e-Silva V, Calado S, Viana-Baptista M. Oral direct thrombin inhibitor as an alternative in the management of cerebral venous throm- bosis: a series of 15 patients. Int J Stroke. 2015 Oct;10(7):1115-8.
52. Lee GKH, Chen VH, Tan CH, et al. Comparing the efficacy and safety of direct oral an- ticoagulants with vitamin K antagonist in cerebral venous thrombosis. J Thromb Thrombolysis. 2020;50(3):724-31.
53. Viegas LD, Stolz E, Canhao P, Ferro JM. Systemic thrombolysis for cerebral venous and dural sinus thrombosis: a systematic review. Cerebrovasc Dis. 2014;37(1): 43-50.
54. Salottolo K, Wagner J, Frei DF, Loy D, Bellon RJ, McCarthy K, et al. Epidemiology, endovascular treatment, and prognosis of cerebral venous thrombosis: US center study of 152 patients. J Am Heart Assoc. 2017 Jun 13;6(6):e005480.
55. Coutinho JM, Zuurbier SM, Bousser M, et al. Effect of endovascular treatment with medical management vs Standard care on severe cerebral venous thrombosis: the TO-ACT randomized clinical trial. JAMA Neurol. 2020;77(8):966-73.
56. Idiculla PS, Gurala D, Palanisamy M, Vijayakumar R, Dhandapani S, Nagarajan E. Ce- rebral venous thrombosis: a comprehensive review. Eur Neurol. 2020 Sep;2:1-11.
57. Ferro JM, Bacelar-Nicolau H, Rodrigues T, et al. Risk score to predict the outcome of patients with cerebral vein and dural sinus thrombosis. Cerebrovasc Dis. 2009;28 (1):39-44.