What causes hemosiderin staining in the brain? Can fMRI safely replace the Wada test for preoperative assessment of language lateralisation? 10.2) will probably further increase the detection rate of epileptogenic substrates such as mesial temporal lobe sclerosis (MTS), focal cortical dysplasia (FCD), and polymicrogyria [811]. What causes hemosiderin staining? Hemosiderin is a stain, left behind after a brain bleed, even after though the blood is reabsorbed into the blood system. Pediatr Neurol. Hemosiderin staining is a medical condition in which one presents yellow or brown patches on the skin. Unfortunately, there are many different encephalomalacia causes. (a, b) Boy, 6months. Malformations related to abnormal cortical organization encompass polymicrogyria, schizencephaly, and FCD type I (non-balloon cell). Imaging of patients with hippocampal sclerosis at 7 Tesla: initial results. Before 8600 Rockville Pike Mehndiratta P, Manjila S, Ostergard T, Eisele S, Cohen ML, Sila C, Selman WR. Submit only on articles published within 6 months of issue date. [, Bauer PR, Reitsma JB, Bernard M, Houweling BM, et al. There will be paucity of the white matter and, as the lesion occurred prior to complete myelination, a relatively mild gliosis. Excess red meat. on the prevalence of epileptogenic lesions among 2740 patients the following pathologies were found: mesial temporal lobe sclerosis (32%), tumors (including low and high grade tumors as well as malformative tumors and benign epilepsy associated tumors) in approximately 17% of patients, cortical dysplasias in 11%, glial scars (including posttraumatic, post-ischemic, post-hemorrhagic, postinfectious/abscess, ulegyria, and postsurgical scars) in 11%, vascular diseases (cavernoma AVM, pial angiomatosis) in 5%, malformations of cortical development including nodular heterotopia, subcortical band heterotopia, polymicrogyria, lissencephaly, pachygyria, agenesis of corpus callosum, craniocephalic malformations, hemiatrophy, lobar dysgenesis, hemimegalencephaly, or hamartomas in 3%, and sequelae of encephalitis in 1% while in approximately 20% no lesion could be detected. Submissions should not have more than 5 authors. Methods: This was a cross-sectional study involving 37 mountaineers in 4 groups: 10 had . 2 Hemosiderin staining. Epub 2020 Aug 3. (ac) Two patients with polymicrogyria. 2014;13:111426. Unauthorized use of these marks is strictly prohibited. No comments have been published for this article. Am J Neuroradiol. Thus, if females present with band heterotopias, genetic counseling may be indicated as half of their male offspring may be affected by anterior agyria. 'Orthopedic Surgeon'. High Incidence of Intracerebral Hemorrhaging Associated with the Application of Low-Intensity Focused Ultrasound Following Acute Cerebrovascular Injury by Intracortical Injection. Hemosiderin staining usually happens on the lower leg, near the ankles, or on your feet. Cogswell PM, Barakos JA, Barkhof F, Benzinger TS, Jack CR Jr, Poussaint TY, Raji CA, Ramanan VK, Whitlow CT. AJNR Am J Neuroradiol. Tuber cinereum hamartomas present with the combination of gelastic seizures and precocious puberty. Lissencephaly with agyria more pronounced in the anterior part of the brain. This test may also be used to evaluate for suspected chronic venous insufficiency[2]. In up to 20% of cases additional epileptogenic pathology is found in patients with mesial temporal lobe sclerosis. Pay-per-view content is for the use of the payee only, and content may not be further distributed by print or electronic means. Results: Most women aged 2050 years consumed less dietary iron than their recommended dietary allowances. As a general discussion of all tumors is beyond the scope of this chapter, we will focus only on three tumors that are commonly associated with seizures: the gangliogliomas, the DNETs, and the tuber cinereum hamartomas. Hemosiderin or haemosiderin is an iron-storage complex that is composed of partially digested ferritin and lysosomes.The breakdown of heme gives rise to biliverdin and iron. Lesions within the cerebellum or brainstem are not known to cause epilepsy. The ipsilateral ventricle is enlarged with an abnormal shape of the frontal horn. Hemosiderin is a pigment formed when hemoglobin breaks down. The longer you wait to seek treatment for your varicose veins, the more likely it is for the staining, or skin discoloration, to become permanent. Epub 2016 May 20. Application of diffusion tensor imaging and tractography of the optic radiation in anterior temporal lobe resection for epilepsy: a systematic review. AAN Members (800) 879-1960 or (612) 928-6000 (International) Since hypertension was also found in all subjects who experienced stroke after presenting with MBs, such patients should be treated with, Cerebral microbleeds (MBs) are small chronic brain hemorrhages, likely caused by, Cerebral microbleeds (CMBs) are increasingly recognized neuroimaging findings, occurring with cerebrovascular disease, dementia, and aging. The band may be thin or thick depending on the amount of arrested neurons during migration. Imaging findings in some of these conditions will be subtle which necessitates both a dedicated imaging protocol (as compared to a standard MR) and an expert experience in reading these types of scans. In patients with medication-refractory epilepsy, structural abnormalities can be seen in up to 85% of cases when employing a dedicated MR imaging protocol and when being read by trained Neuroradiologists. Access for 1 day (from the computer you are currently using) is US$ 39.00. AVMs in the temporal lobe have a higher likelihood of producing seizure due to interference of the normal blood supply and drainage of potentially epileptogenic structures such as the hippocampus. (a) coronal T2; (b) sagittal T1 with gadolinium; well delineated cortical/subcortical bubbly mass in the right frontal lobe with prolonged T2 and no contrast enhancement typical of a DNET. Rasmussens encephalitis is a presumably autoimmune mediated chronic inflammation of the brain that presents with progressive gliosis and volume loss. Cerebral microbleeds (CMBs) are increasingly recognized neuroimaging findings, occurring with cerebrovascular disease, dementia, and aging. Cortical dysplasias (coined type III) can be associated with a ganglioglioma. We have changed the login procedure to improve access between AAN.com and the Neurology journals. MeSH However, 0.4% of the general population will have recurrent and unprovoked seizures that do not respond to medication. Pre-surgical epilepsy evaluation using 3T MRI. [, Guerrini R, Duchowny M, Jayakar P, et al. A conceptual framework for the use of neuroimaging to study and predict pharmacoresistance in epilepsy. After clearing, choose preferred Journal and select login for AAN Members. A dedicated epilepsy protocol is necessary to identify these lesions and the MR should be interpreted in conjunction with EEG, MEG, neuropsychological testing, and clinical semiological data to increase the likelihood of identifying these often very subtle lesions. You must have updated your disclosures within six months: http://submit.neurology.org. Distributing copies (electronic or otherwise) of the article is not allowed. Imaging features are very subtle and only mild focal blurring of the graywhite matter junction may be present. Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment. Imaging in the surgical treatment of epilepsy. Your white blood cells, or immune system cells, can clear up some of the excess. Prevalence of acute neurological complications and pathological neuroimaging findings in critically ill COVID-19 patients with and without VV-ECMO treatment. Zhang X, Liu L, Jiang N, Liu Y, Wang Q, Tang X, Zhai Q, Zhao L. BMC Neurol. 2010;6:53750. Coronal sequences have to be angulated perpendicular to the hippocampal axis to allow hippocampal volume estimation and caution has to be taken that they are oriented in a plane that ensures direct comparison with the contralateral hemisphere. Objective: Based on recent findings of microhemorrhages (MHs) in the corpus callosum (CC) in 3 individuals after nonfatal high-altitude cerebral edema (HACE), we hypothesized that hemosiderin depositions in the brain after high-altitude exposure are specific for HACE and remain detectable over many years. What is the significance of hemosiderin in mild traumatic brain injury? 2022 Sep;43(9):E19-E35. The affected hemisphere has no function and thus hemispherectomy can be proposed to these patients. Gangliogliomas occur in young adults and older children, when present under the age of 10 they are often larger with more cystic components. Your legs are important. Typical symptoms include 2-5: sensorineural hearing loss most common, found in ~95% of patients bilateral and gradual cerebellar dysfunction (ataxia): ~90% pyramidal signs: ~75% other less common findings include dementia bladder incontinence other cranial nerve dysfunction The left hemisphere is enlarged with broad gyri and shallow sulci. In addition, patients may present with choroid plexus hypertrophy and brain hemiatrophy as well as a facial port-wine stain (Fig. On imaging an exophytic smooth ovoid mass in the residual germinal matrix, i.e., along the ventricle is seen (Fig. 10.18). Hemosiderin collects in the skin and is slowly removed after bruising; hemosiderin may remain in some conditions such as stasis dermatitis. It also increases the chance to detect subtle changessee small area with polymicrogyria in the left hemisphere! In our practice, we employ this coronal angulation for both T2FLAIR and T1 IR sequences. (a, b) Hypothalamic hamartoma. As the internal reference (i.e., the contralateral hippocampus) is similarly affected, comparison of the signal with other regions of archicortex (34 layered cortex) can identify whether a mesial temporal lobe sclerosis is present bilaterally. Overall, 15.3% of all subjects had at least 1 CMB. This test is used to evaluate and manage disorders involving the destruction of red blood cells[1]. (a, b) X-linked lissencephaly, boy, 2weeks old. In addition to epilepsy these patients may have developmental delay and focal neurological deficits. The vast majority of patients with epilepsy can be treated satisfactorily with antiepileptic drugs. A variety of non-radiological adjunct tests are available that may help in the localization of the seizure focus and preferably these challenging cases are therefore discussed in multidisciplinary conferences. 1 The blood that is supposed to go up towards the heart flows backward into the veins in the legs, causing blood to pool. Symptoms can vary depending on the distribution of hemosiderin deposition. Taehan Yongsang Uihakhoe Chi. doi: 10.3174/ajnr.A7586. 2012;135:134869. Your email address will not be published. What causes hemosiderin staining? Identification of the second focus is of great importance as failure to do so may result in surgical failure if only a selective amygdalohippocampectomy is performed thus leaving the primary focus behind. 10.5). Brain. In all other subjects, MHs were unequivocally absent. Your organization or institution (if applicable), e.g. The third and last part of the cortical development, the lamination, is the organization of the cells within different cortical layers, a process that is orchestrated by the subplate (the lowest layer of cortex). You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid Selection of narrow window width better optimizes contrast between the gray and white matter which can assist in lesion detection (Fig. Focal areas of signal loss on GE MRI imaging pathologically represent focal hemosiderin deposition associated with previous hemorrhagic events. Similar to the previous paragraph, it is beyond the scope to in detail describe imaging features of vascular malformations, infections or trauma that can go along with seizures and most of the entities are described in other chapters of this syllabus. 2009;50:918. Well delineated smooth ovoid masses lateral to the trigone and temporal horn of the left ventricle. Results: Hemosiderin staining within alveolar macrophages was first detected in the BAL and lung tissue at day 3, peaked at day 7, and persisted through 2 months. 10.1). Correlation of lipoprotein-associated phospholipase A2 and cerebral microbleeds in patients with acute ischaemic stroke. Hemosiderin staining usually happens on the lower leg, near the ankles, or on your feet. The necessity of expert MR reading with a dedicated imaging protocol is further highlighted by the fact that postsurgical seizure freedom is achieved significantly more often when a circumscribed, resectable epileptogenic lesion can be identified on MRI preoperatively compared to patients that are rated non-lesional [3]. CMBs are, Due to neurological decline, this condition is. (a, b) Patient 1. The site is secure. The most notable condition that causes hemosiderin staining is chronic venous insufficiency (CVI). [, Piper RJ, Yoong MM, Kandasamy J, et al. The use of even higher field strengths (7T) (Fig. Epilepsia. 'Royal Free Hospital'. Activation is seen predominantly in the left hemisphere in the frontal language region; typical language lateralization, (a, b) SISCOM: (a) axial T1 with small subcortical area in the right temporal lobe with prolonged T1; (b) co-registration of SPECT on MR-images shows ictal hyperperfused area exactly in the same spot as the suspected lesion. (c, d) Patient 2: ( (more). [, De Ciantis A, Barkovich AJ, Cosottini M, et al. 10.20). 2013;54:197787. 2022 Oct 6;14(10):2120. doi: 10.3390/pharmaceutics14102120. Purchase The transmantle sign is a specific radiologic feature of FCD type II, which is more frequently detected in patients with FCD type IIb than FCD type IIa. The value of repeat neuroimaging for epilepsy at a tertiary referral centre: 16 years of experience. Lines and paragraphs break automatically. It is believed that in these cases the other epileptogenic lesion triggered the mesial temporal lobe sclerosis (similar to febrile seizures as a child can trigger or kindle a mesial temporal lobe sclerosis). As such you may find vascular abnormalities (such as microangiopathy, arteriovenous malformations (AVM), sinus thrombosis, hemorrhage, cavernomas, or stroke), tumors (metastases, primary tumors), infections (encephalitis, meningitis, abscess), sequelae of previous head injury, and toxic or metabolic conditions (e.g., PRES) in these patients. This is actually a protein that is insoluble and contains irons, being produced by the digestion of the hematin by the phagocytes. Hemosiderin is a form of storage iron derived chiefly from the breakdown of erythrocytes, which normally takes place in the splenic red pulp. Your role and/or occupation, e.g. [, Ryvlin P, Cross JH, Rheims S. Epilepsy surgery in children and adults. The junction between cortex and white matter is indistinct and the cortical gray matter may be focally thickened (Fig. If a laser or chemical peel is used, it may take two to three or . Microbleeds are associated with subsequent hemorrhagic and ischemic stroke in healthy elderly individuals. A Cross-Sectional Study in an Unselected Cohort, Neurology | Print ISSN:0028-3878 Hemosiderin staining can occur in people with venous ulcers, which are slow-healing or non-healing wounds caused by blood pooling in the veins. Its caused by blood leaking out of the tiny vessels called capillaries. Indistinct gray/white matter is noted throughout the entire hemisphere, (a, b) X-linked lissencephaly, boy, 2weeks old. Think of getting a glob of ketchup on a white shirt. (a, b) patient 1; (a) coronal T2 with large subcortical area in the right temporal lobe with prolonged T2. 2014;39:51126. This site needs JavaScript to work properly. A meta-analysis and systematic review. Hemosiderin collects in the skin and is slowly removed after bruising; hemosiderin may remain in some conditions such as stasis dermatitis. The staining alone isnt life-threatening, but it can be an indication of a more serious condition. Bethesda, MD 20894, Web Policies Lissencephaly with agyria more pronounced in the anterior part of the brain. Hard windowing of the FLAIR weighted sequences will make identification of the diseased hippocampus easier. Am J Neuroradiol. Chapter 10. doi: 10.1007/978-3-030-38490-6_10, (ac) Some examples of sequences employed in our institutional dedicated epilepsy protocol: (a) coronal T2 FLAIR, perpendicular to the hippocampal axis; (b) axial T1 inversion recovery (IR) parallel to the hippocampal axis; (c) T1 3D image set presented as pancake view for a better overview of the gyral pattern, (a, b) Right hippocampus internal architecture: (a) coronal T2 at 3T showing an inner hypointense layer of the hippocampus representing the stratum lacunosum; (b) at 1.5T the ultrastructural detail of the hippocampus is obscured due to the decreased spatial resolution and SNR, (a, b) Mesial temporal sclerosis (MTS): (a) coronal T2FLAIR shows increased signal in the left hippocampus; (b) axial T1IR demonstrates volume loss in the left hippocampus. Is Chinese Chicken chop suey Keto friendly? Results: Hemosiderin staining within alveolar macrophages was first detected in the BAL and lung tissue at day 3, peaked at day 7, and persisted through 2 months. The blood pools under the skin. ways to boost your brainpower. MTS is characterized with extensive gliosis throughout the cornu ammonis (CA) regions, but early in the course of the disease there is loss of tissue in the stratum pyramidale most pronounced in CA1 region [15]. (e, f) Diagnosis of ganglioglioma was confirmed following mesial sparing temporal lobectomy, Two patients with DNET. 10.14). Hemosiderin is a particle representing an iron storage complex that is formed by the breakdown of hemoglobin or an abnormal metabolic pathway of ferritin. The patches are usually small and may be itchy or painful. It tends to be golden brown, more refractile, and more clumped than melanin (1.79), but the distinction can be difficult at times, requiring special melanin stains or iron stains. The corresponding (more). Ultra-high-field MR neuroimaging. (For instructions by browser, please click the instruction pages below). Diseases of the Brain, Head and Neck, Spine 20202023: Diagnostic Imaging [Internet]. New intra-cavernomatous thrombosis or hemorrhage may lead to change in seizure frequency. Ippolito A, Urban H, Ghoroghi K, Rosbach N, Lingwal N, Adam EH, Friedrichson B, Steinbicker AU, Hattingen E, Wenger KJ. Epilepsia. 10.11). Imaging findings of first-ever seizure patients are in most cases normal, and abnormalities are only present in approximately 15% of patients as seizures can be provoked by fever, sleep deprivation, stroboscopic lights, or drugs. (more). Pre-operative detailed clinical and radiologic assessment is required to determine if there are co-existing abnormalities in the contralateral hemisphere. What Causes Hemosiderin Staining? Semin Thromb Hemost. Two patients with DNET. Patients with previous trauma can experience posttraumatic seizure disorder, especially after having sustained contusional hemorrhages of their temporal lobes as gliosis and hemosiderin staining can cause irritation of the surrounding cortex. A typical example is neurocysticercosis which is a very common cause of focal epilepsy in the developing world. You will be redirected to a login page where you can log in with your AAN ID number and password. Greenberg SM, Eng JA, Ning M, Smith EE, Rosand J. Stroke. The https:// ensures that you are connecting to the To prevent stroke, risk factors should be carefully managed in subjects with MBs factors. Hereditary hemochromatosis (he-moe-kroe-muh-TOE-sis) causes your body to absorb too much iron from the food you eat. [, von Oertzen J, Urbach H, Jungbluth S, et al. Pharmaceutics. Well delineated smooth ovoid masses lateral to the trigone and temporal horn of the left ventricle. . When you are returned to the Journal, your name should appear at the top right of the page. Note that the signal is identical to that of cortex (more). Hemosiderin is also generated from the abnormal metabolic pathway of ferritin.. You quickly wipe it off, stop the spreading. The cortex lining the defect is polymicrogyric with ill-defined margins to the white matter. Further studies to characterize the associated risks of cerebral microhemorrhages in different stroke populations are needed to use this new imaging marker in therapeutic decisions. These capillary blood leaks can be caused by a number of things . The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Nodular calcified neurocysticercosis in the left hippocampus leading to acquired MTS. It is often seen in people with chronic . This pores and skin discoloration stays till the supply (or the diseased veins) is handled. We offer this Site AS IS and without any warranties. Excellent in plane resolution provides detailed imaging of hippocampus, Functional MRI. However, in clinical practice, their diagnostic value, associated risk, and prognostic significance are often unclear. Open Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. Federal government websites often end in .gov or .mil. To understand the limitations of imaging for patients with medication refractory epilepsy if no dedicated Epilepsy MR protocol is used. Cerebral microhemorrhages have been noted in healthy elderly, ischemic cerebrovascular disease, intracerebral hemorrhage (ICH), cerebral amyloid angiopathy (CAA), and in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. 3 Hemosiderosis (hemosiderin deposition) Hemosiderosis is a medical condition resulting from the excessive accumulation of hemosiderin in different parts of the body. Top differential diagnoses for DNETs are cortical dysplasia, ganglioglioma, pilocytic astrocytoma, glioma, neuroepithelial cysts, and dilated VR spaces. They are associated with chromosomal alterations, congenital infections, or in utero ischemia. 2019;40:10606. Red areas indicate activation during a simple word generation task. It is thought that the hemosiderin deposition associated with cavernous angiomas may play a role in triggering seizures. what causes hemosiderin staining in the brain. These patients are potentially treatable with surgery, and surgical intervention is an appropriate consideration for 3% of people who develop epilepsy [1]. As most of these are benign and just by means of location (i.e., within the corticalwhite matter interface and with temporal lobe predilection) cause the seizures, these are often very good candidates for surgery. The blood pools under the skin and leave a residue of hemoglobin that settles in the tissue there. (ac) Coronal T2 images show a small circumscribed hypointense lesion in the left hippocampal head with associated significant volume of the left hippocampus (more). If you do notice leg discoloration, or hemosiderin staining, take action. ResultsMicrobleed prevalence gradually increased with age, from 6.5% in persons aged 45 to 50 years to 35.7% in participants of 80 years and older. Neonatal anoxic ischemia or hypoxemia can cause ulegyriai.e., a scar/defect of the cerebral cortex that mainly involves the cortex in the depth of the sulcus whereas the cortical crowns remain relatively unaffected. Am J Neuroradiol. Histologically confirmed hippocampal structural features revealed by 3T MR imaging: potential to increase diagnostic specificity of mesial temporal sclerosis. Often these patients have some form of cognitive impairment or developmental delay. government site. Surgical outcomes in lesional and non-lesional epilepsy: a systematic review and meta-analysis. Patients present with global developmental delay and seizures. Hemimegalencephaly. Female carriers of the affected X-chromosome present with band heterotopias that is more present in the frontal lobes compared to the parietal lobes. When blood leaks from capillaries, it collects under the skin and the red blood cells break down. sharing sensitive information, make sure youre on a federal ), University Medicine, Gttingen, Germany. Dual pathology may consist also of bilateral mesiotemporal lobe sclerosis as one hemisphere may trigger the other hippocampus to become sclerotic thus constituting bilateral abnormalities. The two phakomatoses commonly associated with seizures are tuberous sclerosis and SturgeWeber syndrome. In addition other conditions such as vascular malformations, certain phakomatoses, encephaloceles, or infections can be present. If you have a subscription you may use the login form below to view the article. In hemimegalencephaly a diffuse hamartomatous overgrowth as a result of abnormal stem cell proliferation is present resulting in broad gyri, shallow sulci, and a blurred graywhite matter junction. Do not be redundant. We disclaim all responsibility for the professional qualifications and licensing of, and services provided by, any physician or other health providers posting on or otherwise referred to on this Site and/or any Third Party Site. This form of harm could result from significant accidents, hemorrhages, botched surgeries, etc. ), and Department of Neurology, Division of Neuroradiology (K.L. You can also try laser treatment or intense pulsed light (IPL) to fade the discoloration. The source of hemorrhage is not apparent in approximately 50% of patients despite extensive examination. (a) axial T2FLAIR with a small, cortical/subcortical, nodular high-signal area in the right parietal lobe close to the postcentral sulcus; (b) coronal T1 with gadolinium shows contrast enhancement (more), Right superior temporal gyrus ganglioglioma in a middle-aged patient. Information on how to subscribe to Neurology and Neurology: Clinical Practice can be found here. They may calcify and enhancement is very rare and if present should lead to more intensive follow-up as the enhancing portion of a DNET may recur following surgery. Did Texas Roadhouse change their chicken critters? Pathophysiology. Clinically, patients present with macrocephaly, hemiplegia, developmental delay, and seizures. Hemosiderin is a particle representing an iron storage complex that is formed by the breakdown of hemoglobin or an abnormal metabolic pathway of ferritin. The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. In essence, hemosiderin staining is an extreme form of bruising. Results: Most women aged 2050 years consumed less dietary iron than their recommended dietary allowances. 10.9) [16]. 2014;85:5818. The findings shown are relatively subtle. 2022 Dec 14;22(1):482. doi: 10.1186/s12883-022-03000-w. Kim E, Van Reet J, Kim HC, Kowsari K, Yoo SS. Excess iron is stored in your organs, especially your liver, heart and pancreas. Clinical features of high-degree centrum semiovale-perivascular spaces in cerebral amyloid angiopathy. Excessive accumulation of hemosiderin is usually detected within cells of the mononuclear phagocyte system (MPS) or occasionally within epithelial cells of the liver and kidney. (a) axial T2 shows the superficial lesion with heterogenous signal; (b) axial T1 with gadolinium shows an associated vascular structure, a DVA; (c) axial SWAN-sequence. A few unequivocal MHs in the splenium of the CC were found in one subject after severe acute mountain sickness, while one subject with high-altitude pulmonary edema and 2 of the extreme altitude climbers had questionable lesions. National Library of Medicine 2004 Jun;35(6):1415-20. doi: 10.1161/01.STR.0000126807.69758.0e.
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