Diana Aguiar de Sousa

Cerebral venous thrombosis

Cerebral venous thrombosis (CVT) has an incidence of 1.32/100,000/years in high-income countries, and higher in middle- and low-income countries. CVT is more frequent in infants and children young adults and females, especially during pregnancy/puerperium. CVT are now being diagnosed with increasing frequency because of the increased awareness and higher use of magnetic resonance imaging (MR) for investigating patients with acute and subacute headaches and new onset seizures. CVT rarely present as a stroke syndrome. Their most frequent presentations are isolated headache, intracranial hypertension syndrome, seizures, a lobar syndrome and encephalopathy. The confirmation of the diagnosis of CVT relies on the demonstration of thrombi in the cerebral veins and/or sinuses by MR/MR venography or veno CT. The more frequent risk factors/associated conditions for CVT are genetic prothrombotic conditions, antiphospholipid syndrome and other acquired prothrombotic diseases, including cancer, oral contraceptives, puerperium and pregnancy, infections and trauma. The prognosis of CVT is in general favorable, as acute death rate is below 5% and only 15% of the patients remain dependent or die. Treatment in the acute phase includes management of the associated condition, anticoagulation with either low molecular weight or unfractionated heparin, treatment of intracranial hypertension, prevention of recurrent seizures and headache relief. In patients in severe condition on admission or who deteriorate despite anticoagulation, local thrombolysis or thrombectomy is an option. Decompressive surgery is lifesaving in patients with large venous infarcts or hemorrhage with impending herniation. After the acute phase, patients should anticoagulated for a variable period of time, depending on their inherent thrombotic risk. CVT patients may experience recurrent seizures. Prophylaxis with anti-epileptic drugs is recommended after the first seizure, in those with hemispheric lesions. There are several ongoing multicenter registries and trials, which will improve evidence-based and patient-centered management of CVT in the near future.

Safety of Pregnancy After Cerebral Venous Thrombosis A Systematic Review

Background and Purpose— Pregnancy and puerperium are associated with an increased risk of venous thrombotic events (VTEs), including cerebral venous thrombosis (CVT). We aimed to systematically review, in pregnant woman with previous CVT, (1) the risk of recurrence of CVT or other VTE; (2) the result of pregnancy; and (3) the association of antithrombotic prophylaxis with these outcomes. Methods— We searched MEDLINE, Cochrane Database of Systematic Reviews, clinicaltrials.gov (from inception to July 2015), and reference lists of included studies and review articles. We considered observational studies reporting original data on the frequency of CVT or other VTE associated with pregnancy or puerperium in women with history of CVT. Results— Thirteen studies were included. A simple pooled analysis of individual patient data and meta-analysis of proportions using a random effect model were performed. (1) 1 CVT recurrences/217 pregnancies (9 per 1000; 95% confidence interval, 3–33) and 5 noncerebral VTE/186 pregnancies (27 per 1000; 95% confidence interval, 12–61). (2) Pregnancy outcome: 33 spontaneous abortions/186 pregnancies (17.7%; 95% confidence interval, 13–24). (3) Data on the risk of CVT/extracerebral VTE according to antithrombotic prophylaxis was limited. Miscarriage did not differ significantly in women undergoing antithrombotic therapy or not (11.3% versus 18.8%; P=0.34). Conclusions— In women with previous CVT, the absolute risk of pregnancy-related venous thrombosis is low but the relative risk of noncerebral VTE is 16-fold higher and the recurrence of CVT is 80-fold higher than the baseline risk described in general population studies. The rate of miscarriage is not significantly different from that estimated for the general population.

New daily persistent headache and radiologically isolated syndrome

New daily persistent headache (NDPH) is a rare form of chronic daily headache that starts acutely and remains daily from the onset. Several authors have suggested that NDPH should be used as a diagnostic umbrella, requiring a particular effort to discern if secondary causes are present [1]. Although headache may motivate the initial brain MRI in patients with Radiological Isolated Syndrome (RIS), new sudden onset daily persistent headaches are rare and have not been associated with RIS. An association between headache and Multiple Sclerosis (MS) has been described [2], both with migraine and tension subtypes. Headache resulting from active plaques in the posterior fossa, particularly with involvement of the periaqueductal grey matter was reported in MS [3, 4] and Clinically Isolated Syndrome (CIS) [5]. However, although MS encompasses a wide range of neurological symptoms, headache is not listed as a cardinal symptom [2]. A 28-year-old female presented to a neurology clinic complaining of daily headache in the previous year. Her past medical history was unremarkable and she denied family history of neurological disease. At the age of 27, during a bus trip, she noticed a sudden onset pressure-like bilateral headache of 8/10 intensity on a visual analogic scale (VAS), localized in the temples and ears, and that never subsided. The pain did not have migranous features, cranial autonomic symptoms or others suggestive of intracranial hypoor hypertension and persisted from the beginning, continuously, with periods of exacerbation and relief without clear triggering factors but no total remissions. Her physical, ENT and neurological examinations were normal and there were no signs of cervical spine hypermobility. No precipitants were identified, including history of extracranial infection, head trauma, surgery or stressful life events. There was no history of analgesic abuse. Initial workup included brain MRI with arterial and venous angiography that identified multiple hyperintense T2 white matter lesions ([9), including in corpus callosum, juxtacortical and periventricular ([3) but no posterior fossa lesions (Fig. 1). None of the lesions were enhanced with gadolinium and there were no other abnormalities. Multimodal evoked potentials were normal. Analytic workup, including routines, autoimmune screening and viral (HIV, CMV, EBV) studies, were unremarkable. CSF opening pressure was 150 mm H2O, three unmatched oligoclonal bands were identified and CSF was otherwise unremarkable. Two years later, her headaches persisted, sometimes accompanied by mild phonophobia and with average daily pain intensity 5–8 out of 10, despite several therapeutic trials with adequate dosages of amitriptyline, topiramate, pregabalin and gabapentin. No episodes of focal neurological symptoms occurred in this period. MRI was repeated and identified new T2 supratentorial lesions, one (subcortical left frontal) enhanced with gadolinium and with diffusion restriction (Fig. 2). Follow-up MRI after 3 months showed evidence of another new enhancing lesion (subcortical left parietal). Considering MRI-based dissemination in time and refractory NDPH, therapy with D. Aguiar de Sousa (&) R. Geraldes R. Gil-Gouveia J. C. de Sá Department of Neurology, Hospital de Santa Maria, University of Lisbon, Av. Prof. Egas Moniz, 1649-035 Lisbon, Portugal e-mail: diana3543@hotmail.com

Safety of Pregnancy After Cerebral Venous Thrombosis Results of the ISCVT (International Study on Cerebral Vein and Dural Sinus Thrombosis)-2 PREGNANCY Study

Background and Purpose— Pregnancy is associated with increased risk of venous thrombotic events, including cerebral venous thrombosis. We aimed to study the complications and outcome of subsequent pregnancies in women with previous cerebral venous thrombosis. Methods— Follow-up study of women with acute cerebral venous thrombosis at childbearing age included in a previously described cohort (International Study of Cerebral Vein and Dural Sinus Thrombosis). Patients were interviewed by local neurologists to assess rate of venous thrombotic events, pregnancy outcomes, and antithrombotic prophylaxis during subsequent pregnancies. Results— A total of 119 women were included, with a median follow-up of 14 years. Eighty-two new pregnancies occurred in 47 women. In 83% (68 of 82), some form of antithrombotic prophylaxis was given during at least 1 trimester of pregnancy or puerperium. Venous thrombotic events occurred in 3 pregnancies, including 1 recurrent cerebral venous thrombosis. Two of the 3 women were on prophylactic low-molecular-weight heparin at the time of the event. Outcomes of pregnancies were 51 full-term newborns, 9 preterm births, 2 stillbirths, and 20 abortions (14 spontaneous). Conclusions— In women with prior cerebral venous thrombosis, recurrent venous thrombotic events during subsequent pregnancies are infrequent.

Cerebral Venous Thrombosis Causing Posterior Fossa Lesions: Description of a Case Series and Assessment of Safety of Anticoagulation

Background: Isolated posterior fossa parenchymal lesions associated with cerebral venous thrombosis (CVT) are rare. Posterior fossa lesions are an independent predictor of death in CVT. We aim to describe the characteristics and outcome of patients with CVT and isolated posterior fossa lesions and assess the safety of anticoagulation in patients with posterior fossa lesions associated with CVT. Methods: We retrieved data from all patients with posterior fossa parenchymal lesions in the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) cohort related to clinical features, therapy and outcome. Fishers exact test was used to evaluate associations. To assess the safety of anticoagulation in CVT patients with posterior fossa lesions we considered all patients with a lesion in this topography, either isolated or with concomitant supratentorial lesions, and compared the rate of new intracranial haemorrhages on repeated imaging with the remaining cohort. Results: Out of 624 patients, 12 had isolated posterior fossa lesions and 14 had posterior fossa lesion with accompanying supratentorial lesions. The lateral sinus was most frequently occluded (n = 11). Involvement of the superior sagittal sinus was significantly less frequent compared to the remaining patients of the cohort (p = 0.013). None of the patients with isolated posterior fossa lesion died but 3 remained dependent on follow-up. Poor outcome (modified Rankin Scale ≥3) was more frequent in patients with any posterior fossa lesion, even when on anticoagulation (29.2% vs. 11.9%; OR 3.04; 95% CI 1.2-7.6; p = 0.018). Of the 24 anticoagulated patients with a posterior fossa lesion, 3 (12.5%) had new haemorrhages on repeated imaging, compared with 30 out of 495 anticoagulated patients (6.1%) without posterior fossa lesions (p = 0.19). Conclusions: We describe the largest series of CVT patients with associated posterior fossa lesions. When compared to anticoagulated CVT patients without posterior fossa lesions, CVT patients with posterior fossa lesions on full anticoagulation did not have a significant increase in the rate of new intracranial haemorrhages.

Frequency of post-stroke electroencephalographic epileptiform activity – a systematic review and meta-analysis of observational studies

Introduction Cerebrovascular diseases are the most frequent risk factor for epilepsy in the elderly, and epileptic phenomenon following stroke is known to worsen the prognosis. Although electroencephalography is the gold standard epilepsy biomarker, it is rarely used in post-stroke studies, and the frequency of post-stroke epileptiform activity is still uncertain. Patients and methods We analysed studies indexed to MEDLINE, Embase, Web of Science, PsycINFO and OpenGrey (up to March 2015), reporting post-stroke electroencephalographic epileptiform activity frequency in adults. Epileptiform activity was classified as ictal (electrographic seizures) and interictal (non-periodic spikes and sharp waves). Data selection, extraction and appraisal were done in duplicate. Random-effects meta-analysis was used to pool frequencies. Results The pooled frequency of post-stroke ictal and interictal epileptiform activity was 7% (95% CI 3%–12%) and 8% (95% CI 4%–13%), respectively. The use of continuous electroencephalogram was not associated with an increased frequency of electrographic seizures (p = 0.05), nor did the management setting (Intensive Care Unit versus non- Intensive Care Unit, p = 0.31). However, studies with continuous electroencephalogram showed a higher frequency of interictal epileptiform activity (p = 0.01). Discussion This study provides the best available estimates of the frequency of post-stroke electroencephalographic epileptiform activity. Due to detection bias, it was not possible to correlate clinical and electrographic seizures. Conclusion The frequency of ictal and interictal epileptiform activity in the electroencephalogram was comparable with previous frequency analyses of clinical seizures. The frequency of ictal epileptiform activity did not change with continuous record or clinical setting, while the frequency of interictal epileptiform activity increased with continuous record.

Response to comment on “Cerebral venous thrombosis in Behcet’s disease: a systematic review” by Afshin Borhani-Haghighi and Anahid Safari

We read with interest the comments by Borhani-Haghighi and Safari, which corroborate the particular character of cerebral venous thrombosis (CVT) in Behçet’s disease (BD). The physiopathology of CVT in BD was beyond the scope of this article. However, we took your suggestion and reviewed in all the included studies the presence of venous infarction or intracranial hemorrhages, including hemorrhagic transformation. This information is presented in Table 1. As Borhani-Haghighi and Safari suspected these intracerebral lesions are absent in most of the cases of CVT in BD. The high frequency of extra-neurologic vascular events in patients with BD and CVT has been repeatedly highlighted, favoring the ‘‘vasculo-Behçet’’ hypothesis. Tunc et al. [1], and Wechsler et al. [2] found this association in 64% of patients with CVT, but only in 36% without CVT. Likewise, Al-Fahad and Al-Araji [3] reported that 55% patients who presented with intracranial hypertension (IH) had other venous thromboses, but this occurred only in 14% of patients with other neurological manifestations. This association was also referred to by Saadoun et al. [4]. However, this author also found that prothrombotic risk factors were present in one-third of patients with CVT and in most (56%) of those relapsing. The odds of thrombosis relapse was higher in those patients with a prothrombotic

Recanalization in Cerebral Venous Thrombosis: A Systematic Review and Meta-Analysis

Background and Purpose— The role of recanalization of the occluded dural sinus or vein in the outcome of patients with cerebral venous thrombosis (CVT) is not established. We aimed to systematically review, in patients with CVT, (1) the recanalization rate and its association with (2) clinical outcome and (3) CVT recurrence. Methods— Systematic search in MEDLINE (Medical Literature Analysis and Retrieval System Online), Cochrane Library, and clinicaltrials.gov (inception to September 2017). We considered cohort studies reporting the recanalization rate in adult patients with CVT treated with anticoagulation. Reported rates of venous recanalization at the last follow-up, functional outcome defined using the modified Rankin scale at last follow-up dichotomized for favorable (0–1) and unfavorable (2–6) outcome, and recurrence rate of CVT according to recanalization status were extracted independently by 2 authors. Meta-analyses of proportions were performed using Freeman-Tukey double arcsine transformation. Functional outcomes according to the recanalization status were compared using meta-analysis and ordinal logistic regression. We conducted sensitivity analyses for time to assessment of recanalization and study quality. Results— Four hundred sixty-eight studies were identified, and 19 studies were included. (1) We found report of 694 patients with recanalization in the follow-up among 818 cases of CVT. The overall pooled proportion of patients achieving recanalization was 85% (95% confidence interval, 80–89; I2=58%). In studies with higher methodological quality, the recanalization rate was 77% (95% confidence interval, 70–82; I2=0%). (2) There was a significant increase in the chance of favorable outcome (modified Rankin scale, 0–1) in patients with recanalization with a pooled odds ratio of 3.3 (95% confidence interval, 1.2–8.9; I2=32%) in the random effects meta-analysis and a common odds ratio of 3.3 (95% confidence interval, 1.7–6.3) in the ordinal logistic regression. (3) Data on CVT recurrence according to recanalization was scarce. Conclusions— The overall rate of recanalization in patients receiving anticoagulation was 85%, but exclusion of severe patients from follow-up imaging is a plausible source of bias. Lack of venous recanalization was associated with worse clinical outcome.

Brush sign in Sturge-Weber syndrome

Dear Editors, We read with great interest the pictorial review by Linscott et al [1], “Imaging patterns of venous-related brain injury in children,” which offers a clear and valuable summary of these patterns. Furthermore, we would like to share with the readers of Pediatric Radiology an imaging pattern related to SturgeWeber syndrome – the brush sign. The brush sign was first described by Morita et al. [2] in 2008 in a T2*-weighted sequence in the context of acute stroke and was defined as asymmetrical visualization of the subependymal and medullary veins in the deep white matter (Fig. 1). This phenomenon was attributed to BOLD (blood-oxygen-level-dependent) effect due to an increase in intravenous deoxyhemoglobin in cases with major vessel occlusion, reflecting an increased oxygen extraction fraction. Later, Horie et al. [3] identified the brush sign in susceptibility-weighted imaging (SWI) of patients with Moyamoya disease and used this sign to assess disease severity by determining the number of conspicuous deep medullary veins. Again, this phenomenon was attributed to increased oxygen extraction as well as to the chronic state of cerebral vasodilation in these patients. Sturge-Weber syndrome is a sporadic condition associated with vascular malformation of the skin, eye and brain that classically includes facial port-wine stain and ipsilateral pial venular angioma. Abnormal development of the cortical veins is a typical feature, and disease progression has been linked to progressive venous occlusion and resulting venous stasis, for which aspirin is recommended by some clinicians [4]. Engorgement of the medullary veins is commonly seen and was previously described in conventional angiography and MRI [5, 6]. This enlargement resembles the brush sign (Fig. 1) and can be detected in T1-W contrast-enhanced imaging (as in girl with known in Linscott et al. [1]) and is also delineated clearly in SWI sequences, which enhance the abnormal neurovasculature and therefore improve the detection of the prominent deep veins [7]. These collateral channels develop early in the disease and, to a certain extent, are efficient in preventing damage to the adjacent cortex [8], as they can be appreciated in imaging before cortical hypometabolism develops [8]. Furthermore, the development of collaterals may also increase as the disease progresses, as seen in a case presented by Mentzel et al. [9], who demonstrated an increase in medullary veins in a follow-up MRI in a neonate in comparison with the initial exam. In conclusion, Sturge-Weber syndrome should be added to the list of diseases causing the brush sign. It develops due to engorgement of the medullary and subependymal veins serving as collateral channels from the cortex to the deep venous system resulting from the progressive occlusion of the abnormal cortical veins, and an increase in local deoxyhemoglobin concentration caused by hypoxia due to venous stasis. To determine whether this sign can facilitate assessment of disease severity, according to the number or the degree of engorgement of conspicuous deep medullary veins, or whether it can be used to monitor therapy (e.g., effect of aspirin), further studies with serial MRI and clinical correlation are required. * Arsany Hakim arsany_hakim@yahoo.com

Access to and delivery of acute ischaemic stroke treatments: A survey of national scientific societies and stroke experts in 44 European countries

Introduction Acute stroke unit care, intravenous thrombolysis and endovascular treatment significantly improve the outcome for patients with ischaemic stroke, but data on access and delivery throughout Europe are lacking. We assessed best available data on access and delivery of acute stroke unit care, intravenous thrombolysis and endovascular treatment throughout Europe. Methods A survey, drafted by stroke professionals (ESO, ESMINT, EAN) and a patient organisation (SAFE), was sent to national stroke societies and experts in 51 European countries (World Health Organization definition) requesting experts to provide national data on stroke unit, intravenous thrombolysis and endovascular treatment rates. We compared both pooled and individual national data per one million inhabitants and per 1000 annual incident ischaemic strokes with highest country rates. Population estimates were based on United Nations data, stroke incidences on the Global Burden of Disease Report. Results We obtained data from 44 European countries. The estimated mean number of stroke units was 2.9 per million inhabitants (95% CI 2.3–3.6) and 1.5 per 1000 annual incident strokes (95% CI 1.1–1.9), highest country rates were 9.2 and 5.8. Intravenous thrombolysis was provided in 42/44 countries. The estimated mean annual number of intravenous thrombolysis was 142.0 per million inhabitants (95% CI 107.4–176.7) and 72.7 per 1000 annual incident strokes (95% CI 54.2–91.2), highest country rates were 412.2 and 205.5. Endovascular treatment was provided in 40/44 countries. The estimated mean annual number of endovascular treatments was 37.1 per million inhabitants (95% CI 26.7–47.5) and 19.3 per 1000 annual incident strokes (95% CI 13.5–25.1), highest country rates were 111.5 and 55.9. Overall, 7.3% of incident ischaemic stroke patients received intravenous thrombolysis (95% CI 5.4–9.1) and 1.9% received endovascular treatment (95% CI 1.3–2.5), highest country rates were 20.6% and 5.6%. Conclusion We observed major inequalities in acute stroke treatment between and within 44 European countries. Our data will assist decision makers implementing tailored stroke care programmes for reducing stroke-related morbidity and mortality in Europe.