ISSN 0017-8748 doi: 10.1111/head.12599 Published by Wiley Periodicals, Inc.
Headache © 2015 American Headache Society
Research Submission Cerebral Venous Thrombosis and Headache – A Case-Series Marco Sparaco, MD; Michele Feleppa, MD; Marcelo E. Bigal, MD, PhD
Background.—Headache happens in the majority of patients with Cerebral Venous Thrombosis (CVT) being sometimes the sole manifestation of the disease. Herein we report a case-series of CVT, focusing on headache characteristics. Methods.—Etiological, clinical, and radiological features of 25 consecutive adult patients with CVT were compiled from August 2005 to December 2013. Diagnosis of CVT was confirmed by brain magnetic resonance imaging and magnetic resonance venography. All patients underwent extensive systematic etiological and genetic work-up at admission. A structured questionnaire about the characteristics of headache was responded by all participants. Results.—Headache was reported by 23 out of 25 (92%) of participants, being by far the most frequent symptom. It was the sole manifestation in nearly one third of the patients (8/25, 32.0%). Headache was typically severe (19/23, 82.6%) and throbbing (16/23, 69.5%), with sudden onset (13/23, 56.5%) and non-remitting (20/23, 86.9%) characteristics. The sinus most frequently involved was the transverse sinus (24/25, 96.0%), either alone or in association with other sinuses. Conclusion.—Headache is the most frequent symptom and sometimes the sole presentation of CVT. Key words: cerebral venous thrombosis, case-series, headache (Headache 2015;55:806-814)
in women younger than 50 years of age, mainly secondary to oral contraceptive use, pregnancy, and puerperium.2-4 The clinical presentation of CVT is extremely variable as a function of age, presence of parenchymal brain lesions, location, magnitude, and characteristics of the clot.1-3,5 Headache is the most frequent symptom (68-90%),6,7 and it may be the sole manifestation of CVT.8,9 It is frequently associated with other neurological signs, such as seizures, papilloedema, focal deficits, and impaired consciousness.3,9 A typical pattern of headache in CVT has not been identified. The outcome of the disorder is quite variable, but advances in diagnosis and therapy decreased its mortality to under 5%.6,10 An accurate and timely diagnosis by magnetic resonance imaging (MRI) is essential
Cerebral venous thrombosis (CVT) is a multifactorial cerebrovascular disease resulting from the interaction between many acquired (eg, pregnancy, malignancies, trauma) and genetic (eg, congenital thrombophilia) risk factors that predispose to one of the individual components of the Virchow’s triad, characterized by endothelial damage, venous stasis, and hypercoagulability.1-3 The annual incidence of CVT is 5/1,000,000 people per million, and the condition accounts for around 1% of all strokes.1 Although the disease may occur at any age, it is more prevalent From the Division of Neurology, Department of Neurosciences, Benevento, Italy (M. Sparaco and M. Feleppa); Global Clinical Development, Migraine and Headaches, Teva Pharmaceuticals, Frazer, PA, USA (M.E. Bigal). Address all correspondence to M.E. Bigal, Global Clinical Development, Migraine and Headaches, Teva Pharmaceuticals, 4269 Arbor Lane, Doylestown, PA 18902, USA, email: [email protected]
Conflict of Interest: Dr. Bigal is a full-time employee of Teva Pharmaceuticals. He reports no conflicts relevant to this paper. Dr. Sparaco and Dr. Feleppa report no relevant conflicts of interest.
Accepted for publication April 6, 2015.
806
Headache to evaluate the extent of sinus involvements and the presence of parenchymal lesions.1 Being a relatively rare disorder, case-series remain important in order to better describe the clinical features and outcomes of the disease. Accordingly, in this study we report on the etiology, clinical presentation, and outcomes of 25 patients with CVT seen in a referral center in Italy. Furthermore, herein, we describe the characteristics of the headache associated to this disease in an attempt to identify headache features useful for an early diagnosis of CVT. We contrast main findings with what has been reported elsewhere.
METHODS Patients with confirmed CVT consecutively admitted to our department from August 2005 to December 2013 had their information reviewed. All of them were initially evaluated with computed tomography (CT) scan or with MRI. Subsequently, as recommended by the American Heart Association/ American Stroke Association (AHA/ASA) 2011 Scientific Statement,1 venographic study with MR venography (MRV) or helical CT venography (CTV) was conducted to confirm the diagnosis and to define the extent of CVT. In order to identify acquired (eg, pregnancy, puerperium, systemic diseases, malignancies, infections, medication use, surgery, trauma, etc.) and/or genetic (eg, congenital thrombophilia) risk factors for CVT, all patients underwent an extensive systematic etiological work-up that included the following assessments: • Biochemical tests = C-reactive protein, erythrocyte sedimentation rate, hemogram, protein C, protein S, antithrombin III, homocysteine, antinuclear antibody, antiphospholipid and/or anticardiolipin antibodies, lupus anticoagulant, PT and aPTT • Serological tests = search for anti-HIV, VDRL, and antibodies against Borrelia and toxoplasma • Cerebro spinal fluid evaluation and culture for required patients Investigations for connective tissue or hematologic disorders, as well as ophthalmology and derma-
807 tology assessments, were conducted when the suspected diagnosis was Behcet’s disease. A total of 23 patients (16 women and 7 men) consented to genetic analysis focusing on the inherited prothrombotic states most frequently associated with adult CVT, such as Factor V Leiden/G1691A, Prothrombin/G20210A, as well as main polymorphisms in the gene encoding the catalytic domain of the methylene tetrahydrofolate reductase (MTHFR) enzyme, such as the MTHFR/C677T and the MTHFR/A1298C. Based on the onset of the symptomatology, CVT was divided in acute (1 month).11 A structured questionnaire about the characteristics of headache (speed of onset, location, severity, associated symptoms) was applied to all patients as soon as the diagnosis of CVT was confirmed. Pain intensity was measured with the 11-point numerical rating scale (NRS) and assessed in 3 grades based on the scale scores (mild = 1-3; moderate = 4-6; severe ≥ 7).12 Headache onset was categorized as being “thunderclap” (sudden onset, reaching maximum intensity within 1 minute), acute (developing in 7) (82.6%) and throbbing in quality (69.5%). Frequently, this symptom had an acute onset (56.5%) and an evolution of continuous type (86.9%). Headache was unilateral in most patients, in agreement with previous reports.8,15 In our series, the vast majority of patients had at least 1 recognized risk factor for CVT, and the proportion of cases with no identified risk factors (8%) was smaller than previously reported (12.5%).1,6 In particular, the prevalence of hereditary prothrombotic conditions was higher in our series (34.7%) than in most others (around 22% of the CVT cases),6,10,16 thus confirming that inherited thrombophilia constitutes one of the main predisposing factor for CVT, either alone or in combination with other risk factors.
812 The role of genetic changes in the etiology of CVT is further appreciated if polymorphisms in the MTHFR gene are included. A high proportion of our patients (65.2%) carried the MTHFR/C677T mutation (40.0% in the homozygous and 60.0% in the heterozygous state). Previous genetic studies have shown that the prevalence of the homozygous state for the MTHFR/C677T mutation in the Caucasian and Chinese population is around 10-12%.17,18 It should be stressed that although several mutations in genes involved in the clotting cascade (eg, Factor V Leiden/G1691A, Prothrombin/G20210A, etc) are definitely linked to the genesis of CVT,16 the association between the MTHFR/C677T polymorphism and this disease still remains controversial. While the MTHFR 677TT genotype has been associated with a 20% increased risk of venous thrombosis overall,18 the association between the MTHFR/C677T mutation and CVT is less clear. Several studies failed to demonstrate that MTHFR/C677T polymorphisms predispose to CVT,19,20 while a recent meta-analysis suggested the association.16 Since reports are few and small, the correlation between the MTHFR/A1298C and CVT21,22 can only be suggested but not confirmed. The MTHFR/C677T polymorphism consists of a C > T substitution at position 677 of the gene encoding the catalytic domain of the MTHFR enzyme (referred to as 677TT) and results in a substitution of alanine to valine that causes an impaired folate binding.18 This polymorphism encodes a thermolabile variant that decreases enzyme activity by 50-65%23,24 and increases plasma homocysteine levels under conditions of low dietary folate.23,24 As a consequence, it is difficult to assess causality (hyperhomocysteinemia due to the homozygous state) in situations of regular dietary intake of folate. In accordance to what has been previously reported,4,25 oral contraceptive use was common (55.5%). It has been demonstrated that estrogens substantially increase the risk of CVT (Odds Ration (OR) 5.59, 95% confidence interval 3.95-7.91; P < .001), and that this risk is dramatically increased in women with an inherited prothrombotic factor, such as Factor V Leiden and Prothrombin/G20210A mutation.26,27 CT scan was the initial neuroimaging test and was normal in 20.8% of cases. Previous studies have
June 2015 shown that the percentage of normal CT in patients with this disease can vary from 14% to 43% due to technique and observer variation.28,29 CT scanning is less reliable for detection of venous thrombosis and lacks specificity.28 Because of its non-invasiveness and sensitivity to venous flow, MRI and MR angiography have been proposed as being the first choice to assess clinically suspected intracranial venous thrombosis and to follow the course of this pathology in all stages of its evolution.28 Using these techniques, TS involvement happened in most cases (96%), either alone or in association with other sinuses thrombosis (Tables 1 and 2). The frequency of TS involvement in CVT is quite variable, ranging from 51% to 88%.30-33 Furthermore, in our series, 40% of the patients had isolated lateral sinus thrombosis and 60% of them presented with isolated headache. In a previous study by Damak et al, proportions were 32% and 45%.33 The mortality rate in our study was low, in agreement with the trend seen elsewhere.6,10 This decline may be explained by better hospital care and availability of neuroimaging.10 Faster identification of disease translates into earlier treatment care, which might avoid the extension of the thrombotic process in the cerebral venous vasculature. The following conclusions are made: (1) A newonset severe and throbbing headache that is progressive in a short period of time should raise the suspicion of CVT and lead to the early use of MRI for patients for its investigation. (2) The disease is often linked to more than 1 risk factor, and as previously described oral contraceptive use is the most common risk factor in women. (3) Hereditary thrombophilia predisposes to CVT, and all patients with this disorder should be tested for inherited prothrombotic state. (4) Early diagnosis and proper use of anticoagulant therapy in CVT reduce mortality and improve outcomes.
STATEMENT OF AUTHORSHIP Category 1 (a) Conception and Design Michele Feleppa; Marco Sparaco (b) Acquisition of Data Michele Feleppa; Marco Sparaco
Headache
813
(c) Analysis and Interpretation of Data Michele Feleppa; Marco Sparaco 10.
Category 2 (a) Drafting the Manuscript Marcelo E. Bigal (b) Revising It for Intellectual Content Michele Feleppa; Marco Sparaco; Marcelo E. Bigal
11. 12.
13.
Category 3 (a) Final Approval of the Completed Manuscript Michele Feleppa; Marco Sparaco; Marcelo E. Bigal
14.
REFERENCES
15.
1. Saposnik G, Barinagarrementeria F, Brown RD, et al. Diagnosis and management of cerebral venous thrombosis. A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42:1158-1192. 2. Stam J. Thrombosis of the cerebral veins and sinuses. N Engl J Med. 2005;352:1791-1798. 3. Bousser MG, Ferro JM. Cerebral venous thrombosis: An update. Lancet Neurol. 2007;6:162-170. 4. Bousser MG, Crassard I. Cerebral venous thrombosis, pregnancy and oral contraceptives. Thromb Res. 2012;130:S19-S22. 5. De Bruijn SFTM, de Haan RJ, Stam J. Clinical features and prognostic factors of cerebral venous sinus thrombosis in a prospective series of 59 patients. J Neurol Neurosurg Psychiatry. 2001;70:105-108. 6. Ferro JM, Canhao P, Stam J, et al. Prognosis of cerebral vein and dural sinus thrombosis: Results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke. 2004;35:664-670. 7. Iurlaro S, Beghi E, Massetto N, et al. Does headache represent a clinical marker in early diagnosis of cerebral venous thrombosis? A prospective multicentre study. Neurol Sci. 2004;25(Suppl. 3):S298S299. 8. Cumurciuc R, Crassard I, Sarov M, Bousser MG. Headache as the only neurological sign of cerebral venous thrombosis: A series of 17 cases. J Neurol Neurosurg Psychiatry. 2005;76:1084-1087. 9. Timóteo A, Inácio N, Machado S, Pinto AA, Parreira E. Headache as the sole presentation of
16.
17.
18.
19.
20.
21.
22.
cerebral venous thrombosis: A prospective study. J Headache Pain. 2012;13:487-490. Coutinho JM, Zuurbier SM, Stam J. Declining mortality in cerebral venous thrombosis: A systematic review. Stroke. 2014;45:1338-1341. Bousser MG. Cerebral venous thrombosis; diagnosis and management. J Neurol. 2000;247:252-258. Loder E, Burch R. Measuring pain intensity in headache trials: Which scale to use? Cephalalgia. 2012;32:179-182. Einhäupl 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: 1229-1235. Rankin J. Cerebral vascular accidents in patients over the age of 60. II. Prognosis. Scott Med J. 1957; 2:200-215. Agostoni E. Headache in cerebral venous thrombosis. Neurol Sci. 2004;25(Suppl. 3):S206-S210. Marjot T, Yadav S, Hasan N, Bentley P, Pankaj Sharma P. Genes associated with adult cerebral venous thrombosis. Stroke. 2011;42:913-918. Zheng Y-Z, Tong J, Do X-P, Pu X-Q, Zhou B-T. Prevalence of methylenetetrahydrofolate reductase C677T and its association with arterial and venous thrombosis in the Chinese population. Br J Haematol. 2000;109:870-874. Den Heijer M, Lewington S, Clarke R. Homocysteine, MTHFR and risk of venous thrombosis: A meta-analysis of published epidemiological studies. J Thromb Haemost. 2005;3:292-299. Cantu C, Alonso E, Jara A, et al. Hyperhomocysteinemia, low folate and vitamin B12 concentrations, and methylenetetrahydrofolate reductase mutation in cerebral venous thrombosis. Stroke. 2004;35:1790-1794. Gouveia LO, Canhão P. MTHFR and the risk for cerebral venous thrombosis: A meta-analysis. Thromb Res. 2010;125:153-158. Yildiz OK, Cevik S, Cil G, Oztoprak I, Bolayir E, Topaktas S. Cerebral venous sinus thrombosis presenting as transient ischemic attacks in a case with homozygous mutations of MTHFR A1298C and CG677T. J Stroke Cerebrovasc Dis. 2012;21:7577. Fekih-Mrissa N, Klai S, Mrad M, et al. Role of methylenetetrahydrofolate reductase A1298C polymorphism in cerebral venous thrombosis. Blood Coagul Fibrinolysis. 2013;24:118-119.
814 23. Arruda VR, von Zuben PM, Chiaparini LC, Annichino-Bizzacchi JM, Costa FF. The mutation Ala677-->Val in the methylene tetrahydrofolate reductase gene: A risk factor for arterial disease and venous thrombosis. Thromb Haemost. 1997;77:818821. 24. Rozen R. Genetic predisposition to hyperhomocysteinemia: Deficiency of methylenetetrahydrofolate reductase (MTHFR). Thromb Haemost. 1997;78: 523-526. 25. Saadatnia M, Tajmirriahi M. Hormonal contraceptives as a risk factor for cerebral venous and sinus thrombosis. Acta Neurol Scand. 2007;115:295-300. 26. Dentali F, Crowther M, Ageno W. Thrombophilic abnormalities, oral contraceptives, and risk of cerebral vein thrombosis: A meta-analysis. Blood. 2006;107:2766-2773. 27. Martinelli I, Sacchi E, Landi G, Taioli E, Duca F, Mannucci PM. High risk of cerebral-vein thrombosis
June 2015
28.
29.
30. 31.
32. 33.
in carriers of prothrombotic-gene mutation and in users of oral contraceptives. N Engl J Med. 1998;338:1793-1797. Saw VPJ, Kollar C, Johnston IH. Dural sinus thrombosis: A mechanism-based classification and review of 42 cases. J Clin Neurosci. 1999;6:480-487. Daif A, Awada A, Al-Rajeh S, et al. Cerebral venous thrombosis in adults: A study of 40 cases from Saudi Arabia. Stroke. 1995;26:1193-1195. Krayenbuhl HA. Cerebral venous and sinus thrombosis. Clin Neurosurg. 1967;14:1-24. Bousser MG, Chiras J, Bories JB, Castaigne P. Cerebral venous thrombosis:A review of 38 cases. Stroke. 1985;16:199-210. Ameri A, Bousser MG. Cerebral venous thrombosis. Neurol Clin. 1992;10:87-111. Damak M, Crassard I, Wolff V, Bousser MG. Isolated lateral sinus thrombosis: A series of 62 patients. Stroke. 2009;40:476-481.
Headache © 2015 American Headache Society
Research Submission Cerebral Venous Thrombosis and Headache – A Case-Series Marco Sparaco, MD; Michele Feleppa, MD; Marcelo E. Bigal, MD, PhD
Background.—Headache happens in the majority of patients with Cerebral Venous Thrombosis (CVT) being sometimes the sole manifestation of the disease. Herein we report a case-series of CVT, focusing on headache characteristics. Methods.—Etiological, clinical, and radiological features of 25 consecutive adult patients with CVT were compiled from August 2005 to December 2013. Diagnosis of CVT was confirmed by brain magnetic resonance imaging and magnetic resonance venography. All patients underwent extensive systematic etiological and genetic work-up at admission. A structured questionnaire about the characteristics of headache was responded by all participants. Results.—Headache was reported by 23 out of 25 (92%) of participants, being by far the most frequent symptom. It was the sole manifestation in nearly one third of the patients (8/25, 32.0%). Headache was typically severe (19/23, 82.6%) and throbbing (16/23, 69.5%), with sudden onset (13/23, 56.5%) and non-remitting (20/23, 86.9%) characteristics. The sinus most frequently involved was the transverse sinus (24/25, 96.0%), either alone or in association with other sinuses. Conclusion.—Headache is the most frequent symptom and sometimes the sole presentation of CVT. Key words: cerebral venous thrombosis, case-series, headache (Headache 2015;55:806-814)
in women younger than 50 years of age, mainly secondary to oral contraceptive use, pregnancy, and puerperium.2-4 The clinical presentation of CVT is extremely variable as a function of age, presence of parenchymal brain lesions, location, magnitude, and characteristics of the clot.1-3,5 Headache is the most frequent symptom (68-90%),6,7 and it may be the sole manifestation of CVT.8,9 It is frequently associated with other neurological signs, such as seizures, papilloedema, focal deficits, and impaired consciousness.3,9 A typical pattern of headache in CVT has not been identified. The outcome of the disorder is quite variable, but advances in diagnosis and therapy decreased its mortality to under 5%.6,10 An accurate and timely diagnosis by magnetic resonance imaging (MRI) is essential
Cerebral venous thrombosis (CVT) is a multifactorial cerebrovascular disease resulting from the interaction between many acquired (eg, pregnancy, malignancies, trauma) and genetic (eg, congenital thrombophilia) risk factors that predispose to one of the individual components of the Virchow’s triad, characterized by endothelial damage, venous stasis, and hypercoagulability.1-3 The annual incidence of CVT is 5/1,000,000 people per million, and the condition accounts for around 1% of all strokes.1 Although the disease may occur at any age, it is more prevalent From the Division of Neurology, Department of Neurosciences, Benevento, Italy (M. Sparaco and M. Feleppa); Global Clinical Development, Migraine and Headaches, Teva Pharmaceuticals, Frazer, PA, USA (M.E. Bigal). Address all correspondence to M.E. Bigal, Global Clinical Development, Migraine and Headaches, Teva Pharmaceuticals, 4269 Arbor Lane, Doylestown, PA 18902, USA, email: [email protected]
Conflict of Interest: Dr. Bigal is a full-time employee of Teva Pharmaceuticals. He reports no conflicts relevant to this paper. Dr. Sparaco and Dr. Feleppa report no relevant conflicts of interest.
Accepted for publication April 6, 2015.
806
Headache to evaluate the extent of sinus involvements and the presence of parenchymal lesions.1 Being a relatively rare disorder, case-series remain important in order to better describe the clinical features and outcomes of the disease. Accordingly, in this study we report on the etiology, clinical presentation, and outcomes of 25 patients with CVT seen in a referral center in Italy. Furthermore, herein, we describe the characteristics of the headache associated to this disease in an attempt to identify headache features useful for an early diagnosis of CVT. We contrast main findings with what has been reported elsewhere.
METHODS Patients with confirmed CVT consecutively admitted to our department from August 2005 to December 2013 had their information reviewed. All of them were initially evaluated with computed tomography (CT) scan or with MRI. Subsequently, as recommended by the American Heart Association/ American Stroke Association (AHA/ASA) 2011 Scientific Statement,1 venographic study with MR venography (MRV) or helical CT venography (CTV) was conducted to confirm the diagnosis and to define the extent of CVT. In order to identify acquired (eg, pregnancy, puerperium, systemic diseases, malignancies, infections, medication use, surgery, trauma, etc.) and/or genetic (eg, congenital thrombophilia) risk factors for CVT, all patients underwent an extensive systematic etiological work-up that included the following assessments: • Biochemical tests = C-reactive protein, erythrocyte sedimentation rate, hemogram, protein C, protein S, antithrombin III, homocysteine, antinuclear antibody, antiphospholipid and/or anticardiolipin antibodies, lupus anticoagulant, PT and aPTT • Serological tests = search for anti-HIV, VDRL, and antibodies against Borrelia and toxoplasma • Cerebro spinal fluid evaluation and culture for required patients Investigations for connective tissue or hematologic disorders, as well as ophthalmology and derma-
807 tology assessments, were conducted when the suspected diagnosis was Behcet’s disease. A total of 23 patients (16 women and 7 men) consented to genetic analysis focusing on the inherited prothrombotic states most frequently associated with adult CVT, such as Factor V Leiden/G1691A, Prothrombin/G20210A, as well as main polymorphisms in the gene encoding the catalytic domain of the methylene tetrahydrofolate reductase (MTHFR) enzyme, such as the MTHFR/C677T and the MTHFR/A1298C. Based on the onset of the symptomatology, CVT was divided in acute (1 month).11 A structured questionnaire about the characteristics of headache (speed of onset, location, severity, associated symptoms) was applied to all patients as soon as the diagnosis of CVT was confirmed. Pain intensity was measured with the 11-point numerical rating scale (NRS) and assessed in 3 grades based on the scale scores (mild = 1-3; moderate = 4-6; severe ≥ 7).12 Headache onset was categorized as being “thunderclap” (sudden onset, reaching maximum intensity within 1 minute), acute (developing in 7) (82.6%) and throbbing in quality (69.5%). Frequently, this symptom had an acute onset (56.5%) and an evolution of continuous type (86.9%). Headache was unilateral in most patients, in agreement with previous reports.8,15 In our series, the vast majority of patients had at least 1 recognized risk factor for CVT, and the proportion of cases with no identified risk factors (8%) was smaller than previously reported (12.5%).1,6 In particular, the prevalence of hereditary prothrombotic conditions was higher in our series (34.7%) than in most others (around 22% of the CVT cases),6,10,16 thus confirming that inherited thrombophilia constitutes one of the main predisposing factor for CVT, either alone or in combination with other risk factors.
812 The role of genetic changes in the etiology of CVT is further appreciated if polymorphisms in the MTHFR gene are included. A high proportion of our patients (65.2%) carried the MTHFR/C677T mutation (40.0% in the homozygous and 60.0% in the heterozygous state). Previous genetic studies have shown that the prevalence of the homozygous state for the MTHFR/C677T mutation in the Caucasian and Chinese population is around 10-12%.17,18 It should be stressed that although several mutations in genes involved in the clotting cascade (eg, Factor V Leiden/G1691A, Prothrombin/G20210A, etc) are definitely linked to the genesis of CVT,16 the association between the MTHFR/C677T polymorphism and this disease still remains controversial. While the MTHFR 677TT genotype has been associated with a 20% increased risk of venous thrombosis overall,18 the association between the MTHFR/C677T mutation and CVT is less clear. Several studies failed to demonstrate that MTHFR/C677T polymorphisms predispose to CVT,19,20 while a recent meta-analysis suggested the association.16 Since reports are few and small, the correlation between the MTHFR/A1298C and CVT21,22 can only be suggested but not confirmed. The MTHFR/C677T polymorphism consists of a C > T substitution at position 677 of the gene encoding the catalytic domain of the MTHFR enzyme (referred to as 677TT) and results in a substitution of alanine to valine that causes an impaired folate binding.18 This polymorphism encodes a thermolabile variant that decreases enzyme activity by 50-65%23,24 and increases plasma homocysteine levels under conditions of low dietary folate.23,24 As a consequence, it is difficult to assess causality (hyperhomocysteinemia due to the homozygous state) in situations of regular dietary intake of folate. In accordance to what has been previously reported,4,25 oral contraceptive use was common (55.5%). It has been demonstrated that estrogens substantially increase the risk of CVT (Odds Ration (OR) 5.59, 95% confidence interval 3.95-7.91; P < .001), and that this risk is dramatically increased in women with an inherited prothrombotic factor, such as Factor V Leiden and Prothrombin/G20210A mutation.26,27 CT scan was the initial neuroimaging test and was normal in 20.8% of cases. Previous studies have
June 2015 shown that the percentage of normal CT in patients with this disease can vary from 14% to 43% due to technique and observer variation.28,29 CT scanning is less reliable for detection of venous thrombosis and lacks specificity.28 Because of its non-invasiveness and sensitivity to venous flow, MRI and MR angiography have been proposed as being the first choice to assess clinically suspected intracranial venous thrombosis and to follow the course of this pathology in all stages of its evolution.28 Using these techniques, TS involvement happened in most cases (96%), either alone or in association with other sinuses thrombosis (Tables 1 and 2). The frequency of TS involvement in CVT is quite variable, ranging from 51% to 88%.30-33 Furthermore, in our series, 40% of the patients had isolated lateral sinus thrombosis and 60% of them presented with isolated headache. In a previous study by Damak et al, proportions were 32% and 45%.33 The mortality rate in our study was low, in agreement with the trend seen elsewhere.6,10 This decline may be explained by better hospital care and availability of neuroimaging.10 Faster identification of disease translates into earlier treatment care, which might avoid the extension of the thrombotic process in the cerebral venous vasculature. The following conclusions are made: (1) A newonset severe and throbbing headache that is progressive in a short period of time should raise the suspicion of CVT and lead to the early use of MRI for patients for its investigation. (2) The disease is often linked to more than 1 risk factor, and as previously described oral contraceptive use is the most common risk factor in women. (3) Hereditary thrombophilia predisposes to CVT, and all patients with this disorder should be tested for inherited prothrombotic state. (4) Early diagnosis and proper use of anticoagulant therapy in CVT reduce mortality and improve outcomes.
STATEMENT OF AUTHORSHIP Category 1 (a) Conception and Design Michele Feleppa; Marco Sparaco (b) Acquisition of Data Michele Feleppa; Marco Sparaco
Headache
813
(c) Analysis and Interpretation of Data Michele Feleppa; Marco Sparaco 10.
Category 2 (a) Drafting the Manuscript Marcelo E. Bigal (b) Revising It for Intellectual Content Michele Feleppa; Marco Sparaco; Marcelo E. Bigal
11. 12.
13.
Category 3 (a) Final Approval of the Completed Manuscript Michele Feleppa; Marco Sparaco; Marcelo E. Bigal
14.
REFERENCES
15.
1. Saposnik G, Barinagarrementeria F, Brown RD, et al. Diagnosis and management of cerebral venous thrombosis. A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42:1158-1192. 2. Stam J. Thrombosis of the cerebral veins and sinuses. N Engl J Med. 2005;352:1791-1798. 3. Bousser MG, Ferro JM. Cerebral venous thrombosis: An update. Lancet Neurol. 2007;6:162-170. 4. Bousser MG, Crassard I. Cerebral venous thrombosis, pregnancy and oral contraceptives. Thromb Res. 2012;130:S19-S22. 5. De Bruijn SFTM, de Haan RJ, Stam J. Clinical features and prognostic factors of cerebral venous sinus thrombosis in a prospective series of 59 patients. J Neurol Neurosurg Psychiatry. 2001;70:105-108. 6. Ferro JM, Canhao P, Stam J, et al. Prognosis of cerebral vein and dural sinus thrombosis: Results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke. 2004;35:664-670. 7. Iurlaro S, Beghi E, Massetto N, et al. Does headache represent a clinical marker in early diagnosis of cerebral venous thrombosis? A prospective multicentre study. Neurol Sci. 2004;25(Suppl. 3):S298S299. 8. Cumurciuc R, Crassard I, Sarov M, Bousser MG. Headache as the only neurological sign of cerebral venous thrombosis: A series of 17 cases. J Neurol Neurosurg Psychiatry. 2005;76:1084-1087. 9. Timóteo A, Inácio N, Machado S, Pinto AA, Parreira E. Headache as the sole presentation of
16.
17.
18.
19.
20.
21.
22.
cerebral venous thrombosis: A prospective study. J Headache Pain. 2012;13:487-490. Coutinho JM, Zuurbier SM, Stam J. Declining mortality in cerebral venous thrombosis: A systematic review. Stroke. 2014;45:1338-1341. Bousser MG. Cerebral venous thrombosis; diagnosis and management. J Neurol. 2000;247:252-258. Loder E, Burch R. Measuring pain intensity in headache trials: Which scale to use? Cephalalgia. 2012;32:179-182. Einhäupl 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: 1229-1235. Rankin J. Cerebral vascular accidents in patients over the age of 60. II. Prognosis. Scott Med J. 1957; 2:200-215. Agostoni E. Headache in cerebral venous thrombosis. Neurol Sci. 2004;25(Suppl. 3):S206-S210. Marjot T, Yadav S, Hasan N, Bentley P, Pankaj Sharma P. Genes associated with adult cerebral venous thrombosis. Stroke. 2011;42:913-918. Zheng Y-Z, Tong J, Do X-P, Pu X-Q, Zhou B-T. Prevalence of methylenetetrahydrofolate reductase C677T and its association with arterial and venous thrombosis in the Chinese population. Br J Haematol. 2000;109:870-874. Den Heijer M, Lewington S, Clarke R. Homocysteine, MTHFR and risk of venous thrombosis: A meta-analysis of published epidemiological studies. J Thromb Haemost. 2005;3:292-299. Cantu C, Alonso E, Jara A, et al. Hyperhomocysteinemia, low folate and vitamin B12 concentrations, and methylenetetrahydrofolate reductase mutation in cerebral venous thrombosis. Stroke. 2004;35:1790-1794. Gouveia LO, Canhão P. MTHFR and the risk for cerebral venous thrombosis: A meta-analysis. Thromb Res. 2010;125:153-158. Yildiz OK, Cevik S, Cil G, Oztoprak I, Bolayir E, Topaktas S. Cerebral venous sinus thrombosis presenting as transient ischemic attacks in a case with homozygous mutations of MTHFR A1298C and CG677T. J Stroke Cerebrovasc Dis. 2012;21:7577. Fekih-Mrissa N, Klai S, Mrad M, et al. Role of methylenetetrahydrofolate reductase A1298C polymorphism in cerebral venous thrombosis. Blood Coagul Fibrinolysis. 2013;24:118-119.
814 23. Arruda VR, von Zuben PM, Chiaparini LC, Annichino-Bizzacchi JM, Costa FF. The mutation Ala677-->Val in the methylene tetrahydrofolate reductase gene: A risk factor for arterial disease and venous thrombosis. Thromb Haemost. 1997;77:818821. 24. Rozen R. Genetic predisposition to hyperhomocysteinemia: Deficiency of methylenetetrahydrofolate reductase (MTHFR). Thromb Haemost. 1997;78: 523-526. 25. Saadatnia M, Tajmirriahi M. Hormonal contraceptives as a risk factor for cerebral venous and sinus thrombosis. Acta Neurol Scand. 2007;115:295-300. 26. Dentali F, Crowther M, Ageno W. Thrombophilic abnormalities, oral contraceptives, and risk of cerebral vein thrombosis: A meta-analysis. Blood. 2006;107:2766-2773. 27. Martinelli I, Sacchi E, Landi G, Taioli E, Duca F, Mannucci PM. High risk of cerebral-vein thrombosis
June 2015
28.
29.
30. 31.
32. 33.
in carriers of prothrombotic-gene mutation and in users of oral contraceptives. N Engl J Med. 1998;338:1793-1797. Saw VPJ, Kollar C, Johnston IH. Dural sinus thrombosis: A mechanism-based classification and review of 42 cases. J Clin Neurosci. 1999;6:480-487. Daif A, Awada A, Al-Rajeh S, et al. Cerebral venous thrombosis in adults: A study of 40 cases from Saudi Arabia. Stroke. 1995;26:1193-1195. Krayenbuhl HA. Cerebral venous and sinus thrombosis. Clin Neurosurg. 1967;14:1-24. Bousser MG, Chiras J, Bories JB, Castaigne P. Cerebral venous thrombosis:A review of 38 cases. Stroke. 1985;16:199-210. Ameri A, Bousser MG. Cerebral venous thrombosis. Neurol Clin. 1992;10:87-111. Damak M, Crassard I, Wolff V, Bousser MG. Isolated lateral sinus thrombosis: A series of 62 patients. Stroke. 2009;40:476-481.
