Cerebral Vein and Dural Sinus Thrombosis in Elderly Patients

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1 Cerebral Vein and Dural Sinus Thrombosis in Elderly Patients José M. Ferro, MD, PhD; Patrícia Canhão, MD; Marie-Germaine Bousser, MD; Jan Stam, MD; Fernando Barinagarrementeria, MD; for the ISCVT Investigators Backgound and Purpose The clinical features and prognosis of cerebral vein and dural sinus thrombosis (CVT) in elderly patients have not been previously described. Methods In a multicenter prospective observational study, we compared clinical and imaging features, risk factors, and outcome of adult patients aged 65 (young and middle-aged patients) and 65 years (elderly patients). Results A total of 624 adult patients with CVT were registered and followed-up for a median of 16 months. Fifty-one (8.2%) were aged 65 years. Presentation as an isolated intracranial hypertension syndrome was less frequent in elderly patients (4/51 versus 139/573, P 0.008), whereas depressed consciousness (17 versus 97, P 0.005), and mental status changes (22 versus 115, P 0.001) were more frequent in the elderly. The prognosis of elderly patients was considerably worse than that of younger patients, as only 49% of elderly patients made a complete recovery (versus 82% in younger patients), whereas 27% died and 22% were dependent at the end of follow-up (versus 7 and 2% respectively in younger patients). Carcinoma (5 cases) was more frequent as a risk factor for CVT in elderly patients (P 0.017). During follow-up, elderly patients were more likely to experience thrombotic events (HR 4.8, 95% CI 1.9 to 11.9) and were less likely to experience severe headaches (HR 0.2, 95% CI 0.02, 0.97). Conclusions Elderly patients with CVT have a distinctive clinical presentation: isolated intracranial hypertension is uncommon, whereas mental status and alertness disturbances are common. The prognosis of CVT is worse in elderly patients. (Stroke. 2005;36: ) Key Words: aged cerebral veins dural sinus elderly malignancy outcome prognosis thrombosis Cerebral vein and sinus thrombosis (CVT) predominates in children and young and middle-aged adults. Some of their associated conditions, such as pregnancy, puerperium, and use of oral contraceptives, 1 are no longer present in elderly patients, whereas others such as malignancy and dehydration may be more frequent. The clinical features, associated conditions, outcome, and prognostic factors in elderly CVT patients have not been described previously. The fact that age 37 years was associated with a less-favorable outcome of CVT 1 and the increasing aging of the world population, prompted us to analyze the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) cohort to describe CVT patterns and features associated with age and to analyze the prognosis of CVT in elderly patients. Methods The organization of the ISCVT has been described in detail in a previous publication. 1 Briefly, ISCVT is a prospective multinational observational study that included 624 consecutive adult patients with symptomatic CVT, who were diagnosed at 89 participating centers in 21 countries, from May 1998 to May Diagnosis of CVT was confirmed by MR/MR venography, conventional or CT venography, surgery, or autopsy. No uniform investigation or treatment protocols were applied to the participants. A list of risk factors for CVT was attached to the inclusion form to assist investigators with the etiological work up (available at: and thrombophilia screening was recommended. Patients were followed-up for at least 6 months. Follow-up visits were performed at 6 months, at 12 months, and yearly thereafter, predominantly by direct interview and observation by the local investigators. During follow-up, disability, 2 death, recurrent symptomatic sinus thrombosis (new symptoms with new thrombus on repeated venogram or MR), other thrombotic events, seizures, headaches requiring bed rest or hospital admission, severe visual loss (quantified with an optometric chart as 4/10), pregnancy, abortion, and current treatments were recorded. Disability was classified according to the modified Rankin (mrs) scale as complete recovery (mrs 0 to 1); partial recovery, independent (mrs 2); dependent (mrs 3 to 5) and death (mrs 6). For patients who had a telephone follow-up, the Rankin Score was assessed by 3 validated questions. 3 Statistical Analysis We compared the young and middle-aged ( 65 years) and elderly ( 65 years) age groups with the 2 test (with Yates correction when necessary) or Fisher exact test for dichotomous data, with the Received May 18, 2005; accepted June 27, From the Department of Neurosciences and Mental Health (J.M.F., P.C.), Hospital Santa Maria, Lisboa, Portugal; Department of Neurology (M.-G.B.), Hôpital Lariboisière Paris, France; Department of Neurology (J.S.), Academic Medical Centre Amsterdam, The Netherlands; and Department of Neurology (F.B.), Instituto Nacional de Neurologia y Neurocirurgia, México City, México. Correspondence to José M. Ferro, Dept of Neurosciences and Mental Health, Hospital Santa Maria, Lisbon, Portugal. jmferro@fm.ul.pt 2005 American Heart Association, Inc. Stroke is available at DOI: /01.STR

2 1928 Stroke September 2005 Mann Whitney U test for ordinal data, and with the Student t test for continuous data. To analyze prognostic factors for the outcome death or dependency at the end of follow-up in elderly patients, we performed survival analysis, using Kaplan Meier and Cox regression statistics. We calculated the hazard ratios (HRs) and 95% CIs for the retained variables, considering all demographic, clinical, imaging variables, and risk factors as possible explanatory variables. Variables associated (P 0.10) with the outcome in the Kaplan Meier statistics were entered into the Cox regression analysis. Data were analyzed with SPSS 12.0 for Windows. Results Baseline Characteristics of Elderly Patients in Comparison With Young and Middle-Aged Patients Of the 624 included patients, 51 patients (8,2%) were aged 65 years: 16 (31%) were between 65 to 69; 18 (35%) between 70 to 74; 13 (26%) between 75 to 79; and 4 (8%) between 80 to 86 years of age. Baseline characteristics are summarized in Table 1 and describes significant differences found in the bivariate analysis comparing the 2 age groups. Male (28 patients) and female (22 patients) elderly patients had a similar age distribution. There were no differences between the elderly and young and middle-aged groups concerning intervals onset-admission and onset-diagnosis, type of diagnostic imaging procedures, lumbar punctures, completeness of the screening for prothrombotic conditions, site and number of occluded sinus and veins, or treatments. The percentage of therapeutically anticoagulated patients was also similar: 80.4% (41/51) for the elderly and 83.6% (479/573) for the young and middle-aged groups. Presentation as an isolated intracranial hypertension syndrome was less frequent in elderly patients, whereas depressed consciousness (admission Glasgow Coma Scale [GCS] 14) and mental status changes were more frequent in the elderly. GCS scores on admission were lower for elderly patients (P 0.001). Among the elderly, CVT was diagnosed earlier in patients with headache than in those without headache, but the difference was not statistically significant (13 versus 23 days; t 1.31, P 0.19). The opposite was found among the young and middle-aged group (24 versus 18 days; t 0.79, P 0.43). The proportion of patients whose neurological condition deteriorated after admission was similar in the 2 age groups (32% for elderly and 22% for young and middleaged patients). However, new or worsening neurological symptoms/signs were different in the 2 age groups: depressed consciousness (15/51 versus 67/573; P 0.001) and mental status disorder (7/51 versus 36/573; P 0.04) were more frequent in the elderly patient group. Length of stay was 10.7 days longer for elderly patients (30.3 versus 19.6 days; P 0.001; 95% CI: 4.9 to 16.7). The most common risk factors for CVT in the elderly were genetic or acquired thrombophilia, malignancies, and hematological conditions, notably polycythemia. The proportion of cases without identified risk factors was significantly higher among elderly patients (Table 2). Outcome of Elderly Patients in Comparison With the Young and Middle-Aged Patients Information on outcome at discharge was available for all patients. Thirty-day mortality (3.9%) and in-hospital mortality (9.8%) in elderly patients were higher, but not significantly, than in younger patients (3.3% and 3.8%, P 0.81 and P 0.10, respectively). At discharge the distribution of the Rankin Scale scores was different in the 2 age groups ( , df 6, P 0.001). The proportion of patients with complete recovery was lower ( , P 0.001) and that of death or dependent was higher ( , P 0.001) among elderly patients (Table 3). At 6 months, the prognosis was also significantly worse for the elderly group (complete recovery: , P 0.001; death or dependent: , P 0.001). At the end of the study (median follow-up: 16 months), we had follow-up information of 98.7% of the patients. Eight patients (1.3%) were lost to follow-up after discharge. Last follow-up was performed by face-to-face interview of 358 patients (61%). There were no differences in the rate, type, or length of follow-up between the 2 age groups. The distribution of the Rankin Scale scores was different in the 2 age groups ( ; df 6; P 0.001), the proportion of complete recovery being lower (P 0.001; HR 0.2; 95% CI 0.1 to 0.4) and that of death or dependency being higher (P 0.001; HR 8.9; 95% CI 4.8 to 16.4) in elderly patients. Of the 14 deaths in elderly patients, 5 were caused by the acute CVT, 1 by the underlying condition (metastatic breast carcinoma), 4 were vascular deaths (sudden death, limb ischemia, hemorrhagic stroke, and systemic hemorrhage in a patient on anticoagulants), 2 died of pneumonia and respiratory failure, and, in 2 patients, the cause of death was unknown. During follow-up, elderly patients were more likely to experience thrombotic events and were less likely to experience severe headaches (Table 4). Prognostic Factors in Elderly Patients The Cox regression analysis for the outcome death or dependency at the end of follow-up retained 2 variables: any parenchymal lesion on admission CT/MRI (HR 4.5; 95% CI 1.2 to 1.6) and no headache at admission (HR 4.3; 95% CI 1.2 to 16.3). This model predicted 68.6% of the unfavorable outcomes. Discussion Using the large data set of this prospective multicenter international study, we described a distinctive clinical presentation of CVT in patients aged 65 years. CVT in such elderly patients rarely presents as isolated intracranial hypertension syndrome, but depressed consciousness and altered mental status are common. The prognosis of elderly patients was worse than that of younger patients: only 49% recovered completely, whereas 22% were dependent and 27% had died at the end of follow-up. Strengths of this study include: (1) large sample size and diversity of participating hospitals in different countries and continents, which diminishes potential inclusion bias; (2) diagnostic confirmation by robust methods in all cases; (3) 98.7% completeness of follow-up. There are, however, some potential limitations: differential effect of age in case ascertainment and previous disability in elderly patients. It is possible that younger subjects reporting of headache were

3 Ferro et al Dural Sinus Thrombosis in Elderly Patients 1929 TABLE 1. Demographic, Clinical, and Imaging Characteristics of Young and Middle-Aged and Elderly Patients (n 573) (n 51) Characteristics No. % No. % P (%) 95% CI Male Developing country to 6 Referral from other hospital to 8 Ethnicity White Black Asian Hispanic Other Symptoms and signs Headache to 14 Visual loss to 14 Papilloedema to 23 Diplopia Stupor or coma From onset to admission GCS score on admission Aphasia Mental-status disorders Left paresis Right paresis Any paresis Bilateral motor signs Focal seizure Seizure with generalization Any seizure Sensory symptoms Other focal cortical sign Isolated intracranial hypertension syndrome to 22 CT/MRI infarct Left hemisphere Right hemisphere Posterior fossa CT/MRI hemorrhage Left hemisphere Right hemisphere Posterior fossa Any parenchymal lesion on CT/MRI Bilateral parenchymal lesions on CT/MRI Posterior fossa parenchymal lesions on CT/MRI and 95% CI are shown only when P investigated sooner and more frequently with MRI than older subjects, leading to a higher identification of cases of CVT presenting with headache in the younger age group. Current practice would advise the opposite, as headaches are less common in the elderly, and, in this age group, headaches are often secondary. 4,5 In fact, elderly CVT patients presenting with headache were diagnosed sooner than those without headache, whereas an opposite trend was seen in younger patients. The intervals between onset, admission, and diagnosis were similar in the 2 age groups, as well as the type of

4 1930 Stroke September 2005 TABLE 2. Risk Factors for CVT in Young and Middle-Aged and Elderly Patients 65Years Risk Factor No. % No. % P (%) 95% CI None identified Multiple ( 1 risk factors) Trombophilia Genetic Acquired Antiphospholipid antibody Nephrotic syndrome Hyperhomocystinemia Malignancy CNS Solid tumor outside CNS Hematological CNS disorders Dural fistulae Venous anomaly Arteriovenous malformation Hematological condition Polycythemia, thrombocythemia Anemia Vasculitis Systemic lupus erythematosus Behçet Disease Rheumatoid arthritis Thromboangeitis obliterans Nonspecified Other inflammatory systemic disorders Intestinal inflammatory disease Sarcoidosis Other systemic disorders Thyroid disease Other Oral contraceptives* to 51 Pregnancy/puerperium* to 21 Infection Central nervous system Ear, sinus, mouth, face and neck Other Mechanical precipitants Lumbar puncture Cranial trauma Jugular catheter occlusion Neurosurgery Drugs Hormone replacement therapy* to 9 Steroid Cytotoxic Other Surgery Dehydration Cases may have more than 1 risk factor. *Percentage among women. and 95% CI are shown only when P CNS indicates central nervous system.

5 Ferro et al Dural Sinus Thrombosis in Elderly Patients 1931 TABLE 3. Outcome at Discharge, 6 Months, and Last Follow-Up for the Two Age Groups Outcome at Discharge (n 624) Outcome at 6 Months (n 616) Outcome at Last Follow-Up (n 624) 65 y, No. (%) 65 y, No. (%) 65 y, No. (%) 65 y, No. (%) 65 y, No. (%) 65 y, No. (%) Modified Rankin Scale (29) 6 (12) 275 (49) 9 (18) 342 (60) 14 (27) (39) 17 (33) 179 (32) 18 (35) 126 (22) 11 (22) 2 91 (16) 5 (10) 45 (8) 4 (8) 46 (8) 1 (2) 3 40 (7) 3 (6) 20 (4) 4 (8) 13 (2) 5 (10) 4 26 (5) 7 (14) 11 (2) 5 (10) 6 (1) 4 (8) 5 7 (1) 8 (16) 1 (0.2) 3 (6) 2 (0.3) 2 (4) Death 22 (4) 5 (10) 34 (6) 8 (16) 38 (7) 14 (27) Complete recovery 387 (68) 23 (45) 454 (80) 27 (53) 468 (82) 25 (22) Death or dependency 95 (17) 23 (45) 66 (12) 20 (39) 60 (10) 25 (22) TABLE 4. neuroradiological technique used to confirm the diagnosis, the completeness of the prothrombotic screening, and the proportion of anticoagulated patients. This indicates that the type and intensity of medical care was similar in the 2 age groups. We did not register systematic information on previous disability. Therefore, disability at the end of the follow-up has to be considered as CVT-related disability on the top of previous disability. The age differences in CVT symptoms were consistent over time: among the elderly, headache was less frequent at admission, as a symptom of worsening in the acute phase and during follow-up, whereas depressed consciousness and mental status changes were more frequent at admission and when elderly patients experienced neurological deterioration. The distinctive clinical presentation of CVT in the elderly cannot be explained by neuroimaging features, such as the site and number of occluded sinus and the presence and type of parenchymal lesions, which were identical in the 2 age groups. The lower frequency of headache in CVT the elderly may be related to (1) decreased likelihood of intracranial hypertension because of the protective presence of brain atrophy or (2) age-related decrease in the prevalence of primary headaches 6,7 and headaches related to cerebrovascular diseases, 8,9 indicating a possible diminished reactivity of the trigeminovascular system in the elderly. Delirium and other mental changes after other acute cerebral and even noncerebral diseases are much more common in the elderly. 10 The clinical picture of bacterial meningitis in aging adults is also distinct: headache is seen in only 50% of the patients, whereas depressed consciousness and confusion are often present. 11 There are several morphological (cortical and hippocampal atrophy, subcortical white matter changes) and biochemical (reduced cholinergic and dopaminergic activity) changes in the elderly brain, as well as changes in the blood brain barrier, cerebral blood flow, and decreased resistance to ischemia, that may make the elderly brain more vulnerable to injury. 11 Following single cortical vein occlusion in the rat, there is an age-related increase in the rate and size of venous infarct, suggesting a greater vulnerability of the aged brain. 12 This study has several implications for practice. CVT must be included in the differential diagnosis of elderly patients presenting with decreased alertness, delirium, or mental changes, because CVT usually does not present in the elderly as headache or isolated intracranial hypertension. Extensive search for cancer should be pursued in the elderly patient with Events During Follow-Up in Young and Middle-Aged and Elderly Patients No. % No. % P HR 95% CI Death Recurrent sinus thrombosis Other thrombotic events Limb or pelvic venous thrombosis Pulmonary embolism Stroke TIA Acute limb ischemia Seizures Severe headache Severe visual loss

6 1932 Stroke September 2005 CVT. Elderly patients are at increased risk of thrombotic events during follow-up. Oral anticoagulation for 6 months 13,14 after the acute phase of CVT may be warranted. This study also underscores the importance of including elderly subjects in clinical studies, where, in general, they are underrepresented. 15 Acknowledgments This study was supported by PRAXIS grant C/SAU/10248/1998 from the Fundação para a Ciência e Tecnologia. We thank the investigators who participated in the ISCVT, the names and centers of whom are listed in a previous publication. 1 References 1. Ferro JM, Canhão P, Stam J, Bousser M-G, Barinagarrementeria F; for the ISCVT Investigators. Prognosis of cerebral vein and dural sinus thrombosis. Results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke. 2004;35: Bamford JM, Sandercock PA, Warlow CP, Slattery J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1989;20: Candelise L, Pinardi G, Aritzu E, Musicco M. Telephone interview for stroke outcome assessment. Cerebrovasc Dis. 1994;4: Edmeads JG. Headache in the elderly. In: Olesen J, Tfelt-Hansen P, Welch KMA, eds. The Headaches. 2nd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2000: Silberstein SD, Lipton RB, Goadsby PJ. Geriatric headache. In: Silberstein SD, Lipton RB, Goadsby PJ, eds. Headache in Clinical Practice. Oxford, UK: Isis Medical Media; 1998: Ziegler DK, Hassanein RS, Couch JR. Characteristics of life headache histories in a nonclinic population. Neurology. 1997;27: Rasmussen BK, Jensen R, Schroll M, Olesen J. Epidemiology of headache in a general population a prevalence study. J Clin Epidemiol. 1991;44: Ferro JM, Melo TP, Oliveira V, Salgado AV, Crespo M, Canhão P, Pinto NA. A multivariate study of headache associated with ischemic stroke. Headache. 1995;35: Melo TP, Pinto AN, Ferro JM. Headache in intracerebral hematomas. Neurology. 1996;47: Inouye S. Predisposing and precipitating factors for delirium in hospitalised older patients. Dement Geriatr Cogn Disord. 1999;10: Choi JY, Morris JC, Hsu CY. Aging and cerebrovascular disease. Neurol Clin. 1998;16: Otsuka H, Nakase H, Nagata K, Ueda K, Kempski O, Sakaki T. Effect of age on cerebral venous circulation disturbances in the rat. J Neurosurg. 2000;93: Agnelli G, Prandoni P, Santamaria MG, Bagatella P, Iorio A, Bazzan M, Moia M, Guazzaloca G, Bertoldi A, Tomasi C, Scannapieco G, Ageno W; Warfarin Optimal Duration Italian Trial Investigators. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. Warfarin Optimal Duration Italian Trial Investigators. N Engl J Med. 2001;345: Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR, Cushman M, Moll S, Kessler CM, Elliott CG, Paulson R, Wong T, Bauer KA, Schwartz BA, Miletich JP, Bounameaux H, Glynn RJ; PREVENT Investigators. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003;348: Duncan PW, Jorgensen HS, Wade DT. Outcome measures in acute stroke trials. A systematic review and some recommendations to improve practice. Stroke. 2000;31:

Early Seizures in Cerebral Vein and Dural Sinus Thrombosis Risk Factors and Role of Antiepileptics

Early Seizures in Cerebral Vein and Dural Sinus Thrombosis Risk Factors and Role of Antiepileptics José M. Ferro, MD, PhD; Patrícia Canhão, MD; Marie-Germaine Bousser, MD; Jan Stam, MD; Fernando Barinagarrementeria,