Transient Focal Neurological Symptoms Research Articles

Migraine Aura-Catch Me If You Can with EEG and MRI-A Narrative Review.

Roughly one-third of migraine patients suffer from migraine with aura, characterized by transient focal neurological symptoms or signs such as visual disturbance, sensory abnormalities, speech problems, or paresis in association with the headache attack. Migraine with aura is associated with an increased risk for stroke, epilepsy, and with anxiety disorder. Diagnosis of migraine with aura sometimes requires exclusion of secondary causes if neurological deficits present for the first time or are atypical. It was the aim of this review to summarize EEG an MRI findings during migraine aura in the context of pathophysiological concepts. This is a narrative review based on a systematic literature search. During visual auras, EEG showed no consistent abnormalities related to aura, although transient focal slowing in occipital regions has been observed in quantitative studies. In contrast, in familial hemiplegic migraine (FHM) and migraine with brain stem aura, significant EEG abnormalities have been described consistently, including slowing over the affected hemisphere or bilaterally or suppression of EEG activity. Epileptiform potentials in FHM are most likely attributable to associated epilepsy. The initial perfusion change during migraine aura is probably a short lasting hyperperfusion. Subsequently, perfusion MRI has consistently demonstrated cerebral hypoperfusion usually not restricted to one vascular territory, sometimes associated with vasoconstriction of peripheral arteries, particularly in pediatric patients, and rebound hyperperfusion in later phases. An emerging potential MRI signature of migraine aura is the appearance of dilated veins in susceptibility-weighted imaging, which may point towards the cortical regions related to aura symptoms ("index vein"). Conclusions: Cortical spreading depression (CSD) cannot be directly visualized but there are probable consequences thereof that can be captured Non-invasive detection of CSD is probably very challenging in migraine. Future perspectives will be elaborated based on the studies summarized.

An Uncommon Presentation of Cryptococcal Meningoencephalitis

Cryptococcal meningoencephalitis (CM) remains a common cause of central nervous system infections. Patients usually present with headache, fever, malaise, and altered mental status over several weeks. Signs are often absent, but they may include meningism, papilledema, cranial nerve palsies, and depressed level of consciousness. Individuals with CM can occasionally present with small vessel vasculitis causing cerebral lesions. The literature regarding patterns of cerebrovascular injury in CM is scarce.We describe a case of CM in which an unusual presentation was observed: transient focal neurological symptoms initially with absence of fever that led to a misleading primary diagnosis of transient ischemic attack. Since neurological symptoms may be a manifestation of a cryptococcal infection, it is necessary to have a high degree of suspicion for this pathology in the presence of focal neurological deficits, even in patients with vascular risk factors, requiring a thorough etiological investigation.

Rheumatoid meningitis: A systematic review and meta-analysis.

Rheumatoid meningitis (RM) is a neurological complication of rheumatoid arthritis (RA). Current evidence is based on case reports and partial reviews. This is a systematic review and meta-analysis following the PRISMA statement. The aim is to describe the characteristics of the disease, including clinical, imaging and laboratory findings, treatment, outcomes and prognosis reported in the literature. In all, 103 studies with 130 cases were included. RM affected adults with an average age of 62years, with or without a previous RA diagnosis. RA activity and time with the disease were associated with a worse prognosis. Most common clinical manifestations were transient focal neurological signs (64.6%), systemic symptoms (51.3%), episodic headache (50.4%) and neuropsychiatric alterations (47.7%). Joint manifestations were present in only 27.4% of cases. Brain magnetic resonance imaging showed unilateral or bilateral involvement, predominantly frontoparietal. Both pachymeninges and leptomeninges were affected, the latter more frequently (82.88%). The laboratory findings included increased levels of rheumatoid factor (89.71%), anti-cyclic citrullinated peptide (89.47%), C-reactive protein (82.54%) and erythrocyte sedimentation rate (81.81%). Cerebrospinal fluid analysis showed an increase in the protein level (76.14%), with pleocytosis (85.19%) of mononuclear predominance (89.19%). Biopsy was performed in 72.52% of the patients. Corticosteroid pulse therapy was the main induction therapy. Disease relapse occurred in 31.17% of patients, whilst 54.54% had a full recovery. Rheumatoid meningitis must be considered in adult patients with or without RA diagnosis, high-dose corticosteroid induction therapy should be installed and maintenance therapy plays a key role. It is not recommended to use anti-TNF as an induction therapy. Nowadays, RM has a significantly better outcome. These findings may aid clinicians in timely RM diagnosis and treatment, thus improving its outcomes.

Current Management and Therapeutic Strategies for Cerebral Amyloid Angiopathy.

Cerebral amyloid angiopathy (CAA) is characterized by accumulation of amyloid β (Aβ) in walls of leptomeningeal vessels and cortical capillaries in the brain. The loss of integrity of these vessels caused by cerebrovascular Aβ deposits results in fragile vessels and lobar intracerebral hemorrhages. CAA also manifests with progressive cognitive impairment or transient focal neurological symptoms. Although development of therapeutics for CAA is urgently needed, the pathogenesis of CAA remains to be fully elucidated. In this review, we summarize the epidemiology, pathology, clinical and radiological features, and perspectives for future research directions in CAA therapeutics. Recent advances in mass spectrometric methodology combined with vascular isolation techniques have aided understanding of the cerebrovascular proteome. In this paper, we describe several potential key CAA-associated molecules that have been identified by proteomic analyses (apolipoprotein E, clusterin, SRPX1 (sushi repeat-containing protein X-linked 1), TIMP3 (tissue inhibitor of metalloproteinases 3), and HTRA1 (HtrA serine peptidase 1)), and their pivotal roles in Aβ cytotoxicity, Aβ fibril formation, and vessel wall remodeling. Understanding the interactions between cerebrovascular Aβ deposits and molecules that accumulate with Aβ may lead to discovery of effective CAA therapeutics and to the identification of biomarkers for early diagnosis.

Cerebral amyloid angiopathy-related transient focal neurological episodes: A transient ischemic attack mimic with an increased risk of intracranial hemorrhage

BackgroundTransient focal neurological episodes (TFNEs) are a recently recognized clinical presentation of cerebral amyloid angiopathy (CAA). Our aim was to describe the clinical and radiological features of a series of patients with AS. MethodsWe included 11 patients presenting with recurrent transient focal neurological symptoms and radiological features related to CAA. ResultsMean age was 76,6 and 5 patients were women. All patients reported transient, stereotyped, and recurrent episodes (6 patients had >10 episodes). Gradual spread of the symptoms was recorded in 9 patients. Initially, 3 patients were misdiagnosed as having recurrent transient ischemic attack (TIA), 6 as having seizures, and 2 as having both. Two patients were prescribed antiplatelet therapy. A cerebral MRI with T2* gradient-recalled echo sequence revealed cortical superficial siderosis (cSS) in 5 patients, cortical microbleeds in 1 patient, and both features in 5 cases. After a median follow-up of 36 months, intracranial hemorrhage (ICH) was recorded in 4 patients. All 4 had cSS in the previous cerebral MRI, and 1 was on antiplatelet therapy. ConclusionCAA-related TFNEs are an underdiagnosed entity, often mimicking TIA, seizures, or migraine aura. This misdiagnosis can lead to the prescription of antiplatelet or anticoagulant therapy, which increases the risk of ICH. Our results suggest that cSS might be a radiological marker that is closely related to an increased risk of bleeding. A T2* gradient-recalled echo MRI should be performed in elderly patients with transient focal neurological symptoms suggestive of CAA.

Factors Associated With Focal Computed Tomographic Perfusion Abnormalities in Supratentorial Transient Ischemic Attacks

Computed tomographic perfusion (CTP) is useful in diagnosis of patients with transient focal neurological symptoms. In acute imaging of patients with a suspected transient ischemic attack (TIA), it remains unclear which patients develop focal perfusion abnormalities (FPA), that is, hypoperfusion or hyperperfusion. We aimed at determining independent factors associated with FPA in patients with supratentorial TIAs. We prospectively collected consecutive patients with supratentorial TIAs defined by the traditional time-based definition who underwent CTP within 24 hours of symptom onset. We recorded demographics, risk factors, clinical features, severity, and timing from onset. We documented the Age, Blood Pressure, Clinical Features, Duration, and Diabetes (ABCD2) scores, vascular territories, and presence of relevant arterial pathology. Variables were tested for an association with FPA with univariate and multivariate analyses. A hundred and ten of 265 patients (42%) with supratentorial TIAs had FPA on CTP. Acute noncontrast computed tomography showed early ischemic lesions in 6%, and acute/subacute magnetic resonance imaging was pathological in 52 of the 109 cases (47.7%) where it was performed. Clinical factors associated with FPA were high-admission National Institutes of Health Stroke Scale (odds ratio [OR], 1.22), right hemispheric TIA (OR, 3.09), and cardioembolic mechanism (OR, 2.19). Persistence of symptoms during CTP (OR, 2.59), shorter duration of TIA (OR, 0.93), major intracranial arterial pathology (OR, 12.5), and extracranial arterial occlusion (OR, 7.44) were also associated with FPA. Supratentorial TIAs are often associated with FPA in CTP, even after symptom resolution. FPAs are frequent in severe TIAs and those associated with cardioembolism or specific arterial pathologies. These findings can help clinicians in accurate diagnosis of TIA and its underlying mechanisms.

Transient Focal Neurologic Symptoms Correspond to Regional Cerebral Hypoperfusion by MRI: A Stroke Mimic in Children

Children who present with acute transient focal neurologic symptoms raise concern for stroke or transient ischemic attack. We present a series of 16 children who presented with transient focal neurologic symptoms that raised concern for acute stroke but who had no evidence of infarction and had unilateral, potentially reversible imaging features on vascular and perfusion-sensitive brain MR imaging. Patients were examined with routine brain MR imaging, MRA, perfusion-sensitive sequences, and DWI. Fourteen (88%) children had lateralized MRA evidence of arterial tree pruning without occlusion, all had negative DWI findings, and all showed evidence of hemispheric hypoperfusion by susceptibility-weighted imaging or arterial spin-labeling perfusion imaging at presentation. These findings normalized following resolution of symptoms in all children who had follow-up imaging (6/16, 38%). The use of MR imaging with perfusion-sensitive sequences, DWI, and MRA can help to rapidly distinguish children with conditions mimicking stroke from those with acute stroke.

Abstract TMP95: Small Vessel Disease Burden and Clinical Symptoms in Cerebral Amyloid Angiopathy Patients Presenting Without Symptomatic Hemorrhage

Introduction: Cerebral amyloid angiopathy (CAA) is a common age-related small vessel disease (SVD). Patients without ICH typically present with transient focal neurological episodes (TFNEs) or cognitive symptoms. We sought to determine if SVD lesion burden differed between CAA patients first presenting with TFNEs versus cognitive symptoms. Methods: A total of 647 patients presenting either to a stroke department (n=205) or an outpatient memory clinic (n=442), were screened for eligibility. Patients meeting modified Boston criteria for probable CAA were included and markers of SVD were quantified including cerebral microbleeds (CMBs), perivascular spaces, cortical superficial siderosis (cSS), and white matter hyperintensities (WMH). Patients were classified according to presentation symptoms (TFNEs vs cognitive). Total CAA-SVD burden was assessed using a validated summary score. Individual neuroimaging markers and total SVD burden were compared between groups using univariable and multivariable models. Results: There were 261 probable CAA patients included. After adjustment for confounders, patients first seen for TFNEs (n=97) demonstrated a higher prevalence of cSS (p<.0001), higher WMH volumes (p=0.03) and a trend towards higher CMBs counts (p=.09). The total SVD summary score was higher in patients seen for TFNEs (adjusted OR per additional score point=1.46, 95%CI [1.16 - 1.84], p=0.013). Conclusion: We present a large cohort of probable CAA patients without ICH and show that those first evaluated for TFNEs bear a higher burden of structural MRI SVD related damage compared to those first seen for cognitive symptoms. This study sheds light on CAA disease phenotypes, adds to the understanding of CAA clinical expression, and sets the basis for future works investigating CAA prognosis amongst phenotypes.

High ABCD2 Scores and In-Hospital Interventions following Transient Ischemic Attack

Background and Purpose: Following transient ischemic attack (TIA), there is increased risk for ischemic stroke. The American Heart Association recommends admission of patients with ABCD² scores ≥3 for observation, rapid performance of diagnostic tests, and potential acute intervention. We aimed to determine if there is a relationship between ABCD² scores, in-hospital ischemic events, and in-hospital treatments after TIA admission. Methods: We reviewed consecutive patients admitted between 2006 and 2011 following a TIA, defined as transient focal neurological symptoms attributed to a specific vascular distribution and lasting <24 h. Three interventions were prespecified: anticoagulation for atrial fibrillation, carotid or intracranial revascularization, and intravenous or intra-arterial reperfusion therapies. We compared rates of in-hospital recurrent TIA or ischemic stroke and the receipt of interventions among patients with low (<3) versus high (≥3) ABCD² scores. Results: Of 249 patients, 11 patients (4.4%) had recurrent TIAs or strokes during their stay (8 TIAs, 3 strokes). All 11 had ABCD² scores ≥3, and no neurological events occurred in patients with lower scores (5.1 vs. 0%; p = 0.37). Twelve patients (4.8%) underwent revascularization for large artery stenosis, 16 (6.4%) were started on anticoagulants, and no patient received intravenous or intra-arterial reperfusion therapy. The ABCD² score was not associated with anticoagulation (p = 0.59) or revascularization (p = 0.20). Conclusions: Higher ABCD² scores may predict early ischemic events after TIA but do not predict the need for intervention. Outpatient evaluation for those with scores <3 would potentially have delayed revascularization or anticoagulant treatment in nearly one-fifth of ‘low-risk' patients.

Síndrome del dedo azul secundario a ateroembolia por colesterol: reporte de un caso y revisión de la literatura

We describe the case of a 68 year-old woman with very high cardiovascular risk. She consulted because of cyanosis in the toes, associated with transient focal neurological symptoms. Evolution had been 5 days. She was hospitalized with the diagnostic impression of blue toe syndrome and critical arterial ischemia of the lower limbs possibly due to embolic events. After an endovascular procedure, she developed sudden neurological impairment due to multiple strokes, as well as acute renal failure. Biopsy of the affected toes revealed cholesterol crystals inside the blood vessels. Based on the case, a short review about the blue toe syndrome and its main cause, atheroembolism, is presented.

Migraine: multiple processes, complex pathophysiology.

Migraine is a common, multifactorial, disabling, recurrent, hereditary neurovascular headache disorder. It usually strikes sufferers a few times per year in childhood and then progresses to a few times per week in adulthood, particularly in females. Attacks often begin with warning signs (prodromes) and aura (transient focal neurological symptoms) whose origin is thought to involve the hypothalamus, brainstem, and cortex. Once the headache develops, it typically throbs, intensifies with an increase in intracranial pressure, and presents itself in association with nausea, vomiting, and abnormal sensitivity to light, noise, and smell. It can also be accompanied by abnormal skin sensitivity (allodynia) and muscle tenderness. Collectively, the symptoms that accompany migraine from the prodromal stage through the headache phase suggest that multiple neuronal systems function abnormally. As a consequence of the disease itself or its genetic underpinnings, the migraine brain is altered structurally and functionally. These molecular, anatomical, and functional abnormalities provide a neuronal substrate for an extreme sensitivity to fluctuations in homeostasis, a decreased ability to adapt, and the recurrence of headache. Advances in understanding the genetic predisposition to migraine, and the discovery of multiple susceptible gene variants (many of which encode proteins that participate in the regulation of glutamate neurotransmission and proper formation of synaptic plasticity) define the most compelling hypothesis for the generalized neuronal hyperexcitability and the anatomical alterations seen in the migraine brain. Regarding the headache pain itself, attempts to understand its unique qualities point to activation of the trigeminovascular pathway as a prerequisite for explaining why the pain is restricted to the head, often affecting the periorbital area and the eye, and intensifies when intracranial pressure increases.

Syncope causes transient focal neurological symptoms.

The prevalence of focal neurology (FN) as a consequence of syncope is unknown. The aim of the study was to determine its prevalence, risk factors and short-term consequences. A consecutive sample of syncope-unit attendees during a 9-month period had detailed diagnostic syncope evaluation as per European Cardiac Society guidelines coupled with assessment for FN present during syncope/pre-syncope by screening questionnaire, follow-up interview and neuroimaging (1.5T magnetic resonance imaging [MRI]). All participants were followed up for 24 months. Risk factors for FN were identified by comparing FN cases with syncope controls without FN (3:1 ratio). Five-hundred and forty consecutively attended for investigation of syncope (n = 401) and pre-syncope (n = 139). Thirty-one (5.7%) had FN events during hypotensive symptoms, mean age 49 years (19-85). The majority of FN cases had vasovagal syncope (VVS); 22 (71%), whereas eight had OH (25.8%) and one (3.2%) had cardiac arrhythmia. Median duration of FN was 15 min (IQR: 34.5). MRI in 28 (90%) was normal and in 3, old cerebral infarction was evident. Risk factors for FN/syncope were frequent syncope (P = 0·008), childhood syncope (P < 0.0005) and delayed diastolic recovery during active stand (P = 0·02). During 24-month follow-up and targeted intervention, no patients developed recurrence of FN. One in 20 patients with syncope/pre-syncope have co-extant FN, which during 24-month follow-up, does not progress to a persistent deficit (>24 h). Awareness of co-occurrence of FN and syncope is important as stroke misdiagnosis results in aggressive anti-hypertensive management and future events may ensue.

Lipoprotein Phospholipase A2 Mass and Activity Are Not Associated with the Diagnosis of Acute Brain Ischemia

Background: Elevated lipoprotein-associated phospholipase A2 (Lp-PLA2) levels are associated with both coronary artery and cerebrovascular diseases. The clinical diagnosis of neurovascular events, specifically transient ischemic attack can be challenging, although there is disagreement among vascular trained neurologists regarding this. Currently, there is no single accurate biomarker for the diagnosis of acute brain ischemia. Aim: We studied the relationship between Lp-PLA2 mass and activity levels and the diagnosis of acute brain ischemia in the acute phase among patients evaluated in the emergency department following transient focal neurological symptoms. Methods: Patients evaluated in our academic center for transient neurological symptoms of possible ischemic mechanism were enrolled with informed consent. Lp-PLA2 mass and activity levels were performed by DiaDexus, Inc. Results: 100 patients were enrolled: 58 were ischemic (30 stroke, 28 TIA), 10 were unknown, and 28 were non-ischemic. Blood samples were collected after a median delay of 23 h (IQR: 17, 36) after symptom onset. The median levels of Lp-PLA2 activity level for ischemic (stroke and TIA) versus non-ischemic events were 186.5 nmol/ml/min (IQR = 153, 216.3) and 169 nmol/ml/min (IQR = 137, 212.5), respectively. The median levels of Lp-PLA2 mass level for ischemic versus non-ischemic events were 202 ng/ml (IQR = 171.6, 226.1) and 192 ng/ml (167.8, 230). The differences in median Lp-PLA2 mass and activity levels were not statistically significant in the ischemic versus non-ischemic patients. Vessel imaging revealed a symptomatic stenosis in 14 patients (10 intracranial and 4 cervical). The median Lp-PLA2 mass and activity levels among patients with a symptomatic stenosis were not significantly higher than the levels measured in TIA/stroke patients without stenosis. Conclusion: The results of our study do not support the early measurement of Lp-PLA2 mass or activity levels for confirming an ischemic etiology in patients experiencing minor or transient focal neurological events.

Migraine and Patent Foramen Ovale: Barking up the Wrong Tree?

Migraine and Patent Foramen Ovale: Barking up the Wrong Tree?

Cerebral amyloid angiopathy: a transient ischaemic attack mimic

Cerebral amyloid angiopathy is a commonly occurring condition that is not familiar to most clinicians. A common presenting feature may be transient focal neurological symptoms leading to the potential for clinical misdiagnosis as transient ischaemic attack. This may result in the inappropriate use of anti-platelets and anticoagulants or radiological misdiagnosis. It is also being increasingly recognised as an important cause of spontaneous intracerebral haemorrhage and cognitive impairment in the elderly. Cerebral amyloid angiopathy can be diagnosed based on clinical and radiological findings, but clinicians need a high index of suspicion to ensure appropriate investigations are requested. In this article we aim to cover the pathophysiology, clinical findings, radiological appearances and approach to management of cerebral amyloid angiopathy.

Transient CNS Deficits and Migrainous Auras in Individuals Without a History of Headache

To demonstrate that benign transient focal neurological symptoms represent equivalents of migraine auras without headache. Benign focal neurological symptoms suggesting cerebral dysfunction are common and usually prompt an extensive diagnostic workup, but their etiology is often not elucidated. We hypothesized that benign transient focal neurological symptoms represent equivalents of migraine auras without headache, even in subjects who have never experienced migraine headaches. We led a cross-sectional study and identified individuals who presented at least 1 episode of unexplained transient focal neurological symptoms suggestive of cerebral dysfunction, but no history of migraine headache, among physicians and inpatients of an academic hospital. Cortical hyperexcitability, assessed by occipital transcranial magnetic stimulation (oTMS), was used as a marker of possible migraine auras without headache. Frequency of transient focal neurological symptoms suggestive of cerebral dysfunction among the physicians who responded was 9% (21/233), vs 0.09% (6/690) of inpatients. Most episodes resembled typical visual migrainous auras. Motor, sensory, and language dysfunction were more common among inpatients than among physicians. oTMS induced phosphenes in 12/16 (75%) subjects and in none of 10 controls. Benign focal neurological symptoms were common in our population and likely represent migraine aura without headache. Non-visual symptoms are less common and lead to medical consultation. oTMS is abnormal in most cases, supporting the diagnosis of migraine aura without headache and helping separate this benign condition from transient ischemic attacks.

Migraine with Aura Phenomenology and Length

About 30 % of patients with migraine suffer from episodes of migraine with aura. Migraine with aura is characterized by transient focal neurologic symptoms, visual, sensory, or dysphasic, more rarely motor or brainstem, called ‘aura’ that are usually followed by a full migraine. The symptoms of the aura phase develop usually progressively over minutes and generally last for 5 to 60 minutes, although in a significant proportion of patients can be longer. The presumed substrate of migraine with aura is cortical spreading depression (CSD), a primarily neuronal phenomenon that causes a progressive shutdown of the cerebral cortex, starting from the occipital area and spreading onward at a speed of 2 to 3 mm per minute. The susceptibility to generate a CSD seems to be an intrinsic property of the migrainous brain.

Recent advances in the management of transient ischaemic attack: a clinical review

Transient ischaemic attack (TIA) if untreated carries a high risk of early stroke and is associated with poorer long-term survival. There have been recent advances in the understanding of TIA, its investigations, management and organisation of services for patient care. Clinically, patients are diagnosed TIA if they have transient sudden-onset focal neurological symptoms which usually completely and rapidly resolve by presentation. Patients with residual symptoms should be evaluated as potentially having stroke, if they present within 4.5 h of onset, should be urgently evaluated for their potential eligibility for thrombolysis. TIA patients should receive rapid attention with essential investigations, including brain imaging, electrocardiograph and carotid ultrasound. Immediate administration of an antiplatelet agent is recommended after brain imaging, with subsequent attention to preventing or treating other mechanistic factors. There is emerging evidence that TIA patients can be managed safely in the outpatient setting after initial rapid management in emergency departments as part of a structured clinical pathway supervised by stroke specialists. Clinical systems of management may require approaches individualised to the healthcare setting, while adopting the central aspects of rapid management.

Cerebral Amyloid Angiopathy With Asymmetric Superficial Hemosiderosis and Transient Focal Neurological Symptoms

Cerebral Amyloid Angiopathy With Asymmetric Superficial Hemosiderosis and Transient Focal Neurological Symptoms

Transient Focal Neurological Episodes, Cerebral Amyloid Angiopathy, and Intracerebral Hemorrhage Risk: Looking beyond TIAs

When most doctors encounter older patients with transient focal neurological symptoms, they usually suspect a diagnosis of transient ischemic attacks or some of their known mimics (including migraine auras or focal seizures). This article emphasizes new observations on transient focal neurological episodes in the context of cerebral amyloid angiopathy, a common but under-recognized small vessel disease most often encountered as a cause of symptomatic lobar intracerebral hemorrhage. Transient focal neurological episodes in cerebral amyloid angiopathy are of clinical and pathophysiological interest because they can mimic transient ischemic attacks, but are probably more often related to bleeding (especially superficial cortical siderosis or focal convexity sub-arachnoid hemorrhage) rather than ischemia. Importantly, such episodes may also herald a very high future risk of symptomatic intracerebral hemorrhage. The article highlights scenarios encountered in clinical practice and discusses implications for patient care including: (a) the value of blood-sensitive magnetic resonance imaging sequences in investigating transient focal neurological episodes; and (b) treatment implications, as giving antiplatelet or anticoagulant drugs for these episodes could increase the risk of serious intracerebral hemorrhage.