1. Background
Cerebral venous thrombosis (CVT) is an uncommon disorder affecting predominantly younger women (1-3). Despite numerous studies conducted around the world, various aspects of patients with CVT including risk factors, diagnosis, treatment and outcome remains challenging. Thus CVT still poses major problems in the emergency room setting (4). Patients with CVT present a remarkably wide spectrum but non-specific signs and symptoms including headaches, seizures, hemiparesis, focal lateralized neurological signs, papilledema and behavioral symptoms such as delirium, amnesia and disturbances in consciousness, which may fluctuate over days. These, all count as other clinical manifestations that can be found depending on the mechanisms of the injury and anatomical location of the lesions (4-6).
2. Objectives
Considering all the above-mentioned information, it is necessary to increase knowledge and review the details of CVT risk factors, manifestations, imaging findings and outcomes. Therefore, the present study was conducted to report on the characteristics of CVT in patients, who were referred to the emergency unit of a hospital.
3. Materials and Methods
In this retrospective cross-sectional case series, we evaluated all consecutive patients admitted to the emergency department of Shohadaye Tajrish Hospital, an educational medical center in northern Tehran, Iran from January 2013 to December 2013. All cases were diagnosed with CVT confirmed with magnetic resonance imaging (MRI) and magnetic resonance venography (MRV). Demographic data, chief complaint and symptoms that lead to the impression of an underlying CVT were identified retrospectively by reviewing case files. The medical and drug history, possible risk factors and neurological physical examination were analyzed considering the findings which led to the suspicion of CVT. Further, thrombus localization and the presence of venous infarcts were registered. Thrombus locations were distinguished based on the existing radiologist reports, prospectively reviewed and confirmed by a neuroimaging specialist. Data collection was performed by a manual search.
All patients were treated by unfractured heparin (manufactured by Alborz Daru Company) with 100 unit/kg as the bolus intravenous dose and 1000 unit/hr intravenous infusion almost after diagnosis confirmation with MRV imaging until appearance of disruption in partial thromboplastin time (PTT) test. Oral warfarin (manufactured by Orion Pharma Company) was administered with a dosage of 5 mg/day at second day of admission and was continued for at least six months. All patients were called for re-examination and re-evaluation in March 2014 with the goal of outcome assessment. Resolving the chief complaints and also positive physical examination findings in re-evaluation was considered as favorable outcomes. Data were registered in the database designed for this purpose and analyzed with SPSS 21.
4. Results
During the period of the study, we identified 19 patients with mean age of 38.7 ± 8.8 years (range: 22-62) predominantly consisting of females (84.2%) with most referrals during the hot summer season (8 of 19 (42.1%)). Among these candidates, three patients (15.8%) presented more than one symptom and the other 16 had only one symptom. Demographic data, chief complaint, other symptoms, medical history and physical examination findings are summarized in Table 1. Anatomical locations of the thrombus are listed in Table 2, this information was extracted based on the candidates existing radiologist reports, reviewed and confirmed by a neuroimaging specialist. Superior sagittal and right transverse sinuses were the most commonly involved. Multiple sinuses were involved in five patients (26.3%). Their details are presented separately in Table 3.
After reviewing the radiologists reports on all brain computed tomography scans, it became clear that eight out of 19 cases (42.1%) had abnormalities possibly involving CVT while the other 11 (57.9%) had normal radiologist reports on this type of imaging. In one of the above mentioned abnormal brain CT scans, bilateral thalamus infarct was reported which is considered as a rare presentation for CVT. Among these patients, there were four cases with confusing hemorrhagic patterns in their brain computed tomography scans. Their details are presented separately in Table 4. Between these cases, four of 19 (21%) did not have headaches neither as the chief complaint nor in detailed history of present illness. Their details are presented separately in Table 5.
Use of oral contraceptive pills (OCPs), which is currently considered as an important and prevalent risk factor, was reported in more than half of the cases (10 of 19 cases (52.6%)). Mean follow up period was 6.9 ± 2.9 months (range 4 to 12 months). One of the patients, a 37-year-old female with the diagnosis of right transverse sinus thrombosis, was suffering from visual disturbance for a period of five months at the time of re-evaluation despite appropriate remedial measures. Finally 18 out of 19 patients had favorable outcomes and multinomial logistic regression test showed effectiveness of therapeutic intervention (P = 0.005). There were no reports regarding hospital mortalities resulting from CVT. Surprisingly, all patients had no disturbances on their follow up conducted laboratory tests.
Table 1. Details of Cerebral Vein Thrombosis Patients a
| Variables | Values |
|---|---|
| Gender | |
| Female | 16 (84.2%) |
| Male | 3 (15.8%) |
| Chief complaint | |
| Headache | 15 (78.9%) |
| Hemiparesis | 2 (10.5) |
| Altered mental status | 1 (5.2%) |
| Seizer | 2 (10.5) |
| Visual disturbance | 2 (10.5) |
| Medical history | |
| Hypertension | 2 (10.5) |
| Colorectal cancer | 1 (5.2%) |
| Hypothyroidism | 1 (5.2%) |
| Physical examination | |
| Papilla edema | 11 (57.9%) |
| Nerve palsies | 5 (26.3%) |
| Visual field deficit | 8 (42.1%) |
a Data are Presented as No. (%).
Table 2. Thrombus Location Distribution a
| Thrombus Location | Values |
|---|---|
| Superior sagittal | 7 (28%) |
| Right transverse | 7 (28%) |
| Left transverse | 6 (24%) |
| Right sigmoid | 2 (8%) |
| Inferior sagittal | 1 (4%) |
| Left straight | 1 (4%) |
| Left trolard | 1 (4%) |
a Data are Presented as No. (%).
Table 3. Details of Patients With Multiple Sinuses Thrombosis
| Cases | Gender | Age, y | Chief Complaint | Medical History | OCP or Hormone Use | Physical Examination | Thrombus Location |
|---|---|---|---|---|---|---|---|
| 1 | Female | 30 | Headache | Negative | Positive | Papilla edema, visual field deficits | Superior sagital, right transverse |
| 2 | Female | 41 | Headache | Negative | Positive | Papilla edema | Right sigmoid, right transverse |
| 3 | Female | 41 | Headache | Negative | Positive | Negative | Superior sagital, left transverse |
| 4 | Female | 37 | Headache | Negative | Negative | Nerve palsies | Superior sagital, inferior sagittal |
| 5 | Female | 44 | Headache, visual disturbance | Negative | Positive | Papilla edema, visual field deficits | Left straight, left transverse |
Table 4. Details of Patients With a Hemorrhagic Pattern in Brain Computed Tomography Scan
| Cases | Gender | Age, y | Chief Complaint | Medical History | OCP or Hormone Use | Physical Examination | Thrombus Location |
|---|---|---|---|---|---|---|---|
| 1 | Female | 42 | Headache | Negative | Negative | Papilla edema, nerve palsies, visual field deficits | Left trolard |
| 2 | Female | 22 | Headache, altered mental status | Negative | Positive | Nerve palsies | Superior sagital |
| 3 | Female | 38 | Headache | Negative | Negative | Papilla edema, visual field deficits | Right transverse |
| 4 | Female | 35 | Seizer, hemiparesis | Negative | Positive | Nerve palsies | Superior sagital, left transverse |
Table 5. Details of Patients Without Headaches
| Cases | Gender | Age, y | Chief Complaint | Medical History | OCP or Hormone Use | Physical Examination | Thrombus Location |
|---|---|---|---|---|---|---|---|
| 1 | Female | 47 | Hemiparesis | Negative | Positive | Nerve palsies | Superior sagital |
| 2 | Male | 41 | Seizer | Colorectal cancer | Negative | Papilla edema | Right transverse |
| 3 | Female | 37 | Visual disturbance | Negative | Negative | Papilla edema, visual field deficits | Right transverse |
| 4 | Female | 35 | Seizer, hemiparesis | Negative | Positive | Nerve palsies | Superior sagital, left transverse |
5. Discussion
5.1. Presentation
No set of symptoms has adequate sensitivity or specificity in dealing with the possible diagnosis of CVT, yet headaches plus papilledema, headaches plus diplopia, headaches plus seizure and focal neurological deficit plus papilledema have been mentioned in previous literature as suggestive combinations (4). The clinical presentation of CVT can be highly variable and usually defined by two mechanisms: 1) increased intracranial pressure due to impaired venous drainage 2) focal brain injury caused by venous ischemia/infarction or hemorrhage. Almost always, both mechanisms are involved in the patient’s clinical findings, either at presentation or later in the course of the disease. Location and size of the lesion may also affect the type of symptoms. Headache, as an indication for increased intracranial pressure, is the most prevalent symptom and often has a vague and progressive pattern solely or in combination with other symptoms (7). However, thunderclap headache mimicking subarachnoid hemorrhage and migrainous type has also been reported. Seizure accompanied with focal findings consistent with stroke is rare and highly suggestive of CVT; this is frequently seen with sagittal sinus and cortical veins thrombosis (8-10).
Sensory deficits are less frequent but on the other hand, motor weaknesses including hemiparesis is the most common focal finding. Aphasia resulting from left transverse sinus thrombosis and psychosis, in conjunction with focal neurological signs, has also been reported (4, 11, 12). Thrombosis of the straight sinus and its related branches, large venous infarcts, parenchymal hemorrhages and presence of extensive cerebral edema are possible risk factors for encephalopathy. Elderly in contrast with younger patients are more likely to present an altered mental status (13). In our study, consistent with previous reports, headache was the most prevalent symptom as solely the primary presentation or in combination with other symptoms.
5.2. Risk Factors
Predisposing causes of CVT are numerous and can be categorized in the manner summarized in Table 6 (3, 7, 13-15). Based on the current evidence, inherited thrombophilia, use of oral contraceptives and hyperhomocysteinemia are well-known and more prevalent risk factors than the others (7, 12). Considerable numbers of non-pregnant women with the diagnosis of CVT were using oral contraceptive pills, so it is clear that the use of these agents is associated with an increased risk and this risk is greater if accompanied with the presence of hereditary prothrombotic factors (3, 7). In contrast with numerous confirmative data (3, 7, 14, 16), in rare published manuscripts, like the one belonging to Youssef Sidhom et al. that was conducted on Tunisian patients, thrombophilia, infections, and postpartum state were also mentioned as prominent risk factors, but oral contraceptive use was not a major risk factor in the studied population (17). Akihiro Shindo et al. also found that CVT in Japanese patients is frequently associated with heredity thrombophilia and protein S gene mutation (12). In our study, consistent with some other studies conducted in Iran, oral contraceptives use was an undeniable risk factor.
Table 6. Cerebral Venous Thrombosis Risk Factors
| Categories | Subtypes |
|---|---|
| Thrombophilia | Inherited, (Deficiencies of antithrombin III, protein C, and protein S; Factor V Leiden mutation) |
| Acquired, (Antiphospholipid and anticardiolipin antibodies, Hyperhomocysteinemia) | |
| Women’s health concerns | Pregnancy |
| Postpartum state | |
| Hormonal contraceptive use | |
| Infectious disorders | Localized, (Otitis, Mastoiditis, Sinusitis, Meningitis) |
| Systemic | |
| Chronic inflammatory diseases | Vasculitides, (Systemic lupus erythematosus behcet disease) |
| Inflammatory bowel disease | |
| Hematologic disorders | Polycythemia |
| Thrombocythemia | |
| Iron deficiency anemia | |
| Essential thrombocytosis | |
| Paroxysmal nocturnal hemoglobinuria | |
| Trauma | Local injury to cerebral sinuses or veins |
| Jugular venous cannulation | |
| Neurosurgical procedures | |
| Lumbar puncture | |
| Head trauma | |
| Nephrotic syndrome | - |
| Malignancy | - |
5.3. Diagnosis
Diagnosis can be made from brain computed tomography (CT) scans that may demonstrate venous infarcts or its specific hemorrhages or alternatively allow detection of a different diagnosis. The CVT should be suspected in the setting of multiple hemorrhagic infarctions in one hemisphere without a source of embolism or atherothrombosis or in multiple infarctions on both sides (5, 18). However it has poor sensitivity and shows direct signs of cerebral venous thrombosis in less than half of the cases (7).
No one can rule out CVT with a normal plain brain CT or MRI, and venographic imaging should always be performed in probable cases, while it may also help distinguish normal anatomic variants like hypoplastic sinus (Class I; level of evidence C) (7, 14). The AHA/ASA 2011 Scientific Statement recommends magnetic resonance (MR) with T2 weighted imaging and MR venography as the imaging test of choice for evaluation of suspected cerebral-venous thrombosis. It is also suggested that Gradient echo T2 susceptibility weighted images accompanied with other sequences may promote the accuracy of diagnosis (Class II a; level of evidence B) (7, 18-20). CVT imaging findings on MRI in acute, subacute and chronic phases are summarized in Table 7 (7, 8).
Table 7. Magnetic Resonance Imaging Finding of Cerebral Venous Thrombosis in Various Phases of the Disease
| Phase Type | T1-Weighted | T2-Weighted |
|---|---|---|
| Acute phase | Isointense | Hypointense |
| Sub-acute phase | Hyperintense | Hyperintense |
| Chronic phase | Heterogeneous with variable intensity | Heterogeneous with variable intensity |
5.4. Management
In suspected patients with CVT diagnosis, blood samples should be send for assessing complete blood count, chemistry panel, prothrombin time (PT), and activated partial thromboplastin time (aPTT) (Class I; level of evidence C) (7). Evaluation for deficiencies of protein C, S, and antithrombin in the acute phase and during treatment with warfarin usually leads to negative results and should preferably be delayed until 2 to 4 weeks after completion of anticoagulation (6, 21-23).
Initial anticoagulation with unfractured heparin (UFH) or low molecular weight heparin (LMWH) in full anticoagulant doses is the only proven therapy for patients with CVT that should be followed, regardless of the presence of Intra cranial hemorrhage (ICH) (Class II a; Level of Evidence B) (7, 24). Appropriate anticoagulation is generally not accompanied by any additional risk of intra cranial hemorrhage (5). In patients with severe involvement of multiple sinuses and veins, anticoagulation alone has limited effects on the lysis of deep cerebral venous thrombosis, thus thrombolytic therapy combined with anticoagulation may be more effective (18, 25, 26).
Due to the lack of randomized controlled trials with the aim of assessing the proper anticoagulation period for CVT treatment, guidelines should be prepared based on the evidences and recommendations for other venous thromboembolism (VTE) such as deep vein thrombosis and pulmonary embolism. The AHA/ASA 2011 Scientific Statement recommends anticoagulation with a target international normalized ratio (INR) of 2.0 to 3.0 for 3 to 6 months following the acute phase for patients with the first time CVT without any known risk factors and 6 to 12 months for those with severe coagulopathy or recurrent CVT (7, 24).
Women with a history of oral contraceptive pills use should be recommended for alternative non-estrogen based contraception methods. Women with a history of CVT while receiving hormonal contraceptive, who presented symptoms during pregnancy or in the postpartum period, are at additional risk of recurrence during the next pregnancies. The low-molecular-weight heparin (LMWH) as a prophylactic agent is often recommended during future same courses. The AHA/ASA 2011 Scientific Statement recommends follow up imaging to evaluate recanalization 3 to 6 months after treatment initiation (7, 14). In the case of clinical deterioration, despite intensive anticoagulation treatment, local thrombolysis and mechanical thrombectomy may be considered, yet clinical efficacy is supported only by case reports (Class II b; level of evidence C) (7, 24).
5.5. Outcome
Early diagnosis and prompt appropriate treatment are usually associated with a good prognosis, but the scarcity and various manifestations of CVT may lead to delay in the treatment initiation. Rare numbers of hemorrhagic cases that are often misdiagnosed as intracranial hemorrhage contribute to such delays. Markedly decreased levels of consciousness on presentation, hemorrhagic pattern on primary brain CT scan, delay in diagnosis and therefore in treatment, are poor prognostic factors (5, 25, 27, 28).
Also, many risk factors are known today but it seems that there is different ethnic frequency patterns and inter-racial comparison studies are still needed. Likewise with attention to the lack of proper studies and strong evidence in the field of treatment options, conducting a multicenter prolonged study with a large sample size is apparently required.
