In the pivotal clinical trials of intravenous tissue plasminogen activator (TPA) therapy, a low rate of early arterial recanalization was suspected because only a few stroke patients may have had early dramatic clinical improvement. Tissue plasminogen activator activity can be enhanced with ultrasound, including 2 MHz transcranial Doppler (TCD). Transcranial Doppler identifies residual blood flow signals around thrombi, and, by delivering mechanical pressure waves, exposes more thrombus surface to circulating TPA. For the first time in clinical medicine, the international multicenter CLOTBUST trial showed that ultrasound enhances the thrombolytic activity of a drug in humans, thereby confirming multidisciplinary experimental research conducted worldwide for the past 30 years. In the CLOTBUST trial, the dramatic clinical recovery from stroke coupled with complete recanalization within 2 h after TPA bolus occurred in 25% of patients treated with TPA+TCD compared with 8% who received TPA alone (P=0.02). Complete clearance of a thrombus and dramatic recovery of brain functions during treatment are feasible goals for ultrasound-enhanced thrombolysis that can lead to sustained recovery. An early boost in brain perfusion seen in the target CLOTBUST group resulted in a trend of 13% more patients achieving favorable outcome at 3 months. To further enhance the ability of TPA to break up thrombi, current ongoing clinical trials include phase II studies of 2 MHz TCD with ultrasound contrast agents or (microbubbles): TCD+TPA+Levovist; TCD+TPA+MRX nano-platform (C(3)F(8)). Intra-arterial TPA delivery can be enhanced with 1 x 7-2 x 1 MHz pulsed wave ultrasound (EKOS catheter, IMS trial). Dose escalation studies of microbubbles, ultrasound exposure, and the development of an operator-independent ultrasound device are underway.
Deep venous thrombosis and pulmonary emboli are common preventable causes of morbidity and mortality in patients with acute intracerebral hemorrhage (ICH). The frequency of venous thromboembolism (VTE) in patients with acute ICH ranges from 0.5 to 13% in scant reports. The dilemma in the prevention and treatment of these complications is to reduce the morbidity of VTE without increasing the risk of intracranial rebleeding. There is a paucity of information about this issue, and the applicability of the recommendations for patients with ischemic stroke to those with ICH is unclear. From the available literature, the recommendations for prevention of VTE in patients with ICH are early mobilization, adequate hydration, pneumatic compression stockings, and (in stable patients) low-dose subcutaneous heparins. Considering the treatment of VTE in patients with ICH, placement of an inferior vena caval filter is the most frequent expert recommendation. While existing data are sparse and not sufficient to recommend modifications to current options, the way is open for randomized trials to test early use of antithrombotic agents for VTE in acute ICH patients.
Alopecia areata (AA) is an autoimmune, nonscarring hair loss disorder with slightly greater prevalence in children than adults. Various treatment modalities exist; however, their evidence in pediatric AA patients is lacking.To evaluate the evidence of current treatment modalities for pediatric AA.We conducted a systematic review on the PubMed database in October 2019 for all published articles involving patients <18 years old. Articles discussing AA treatment in pediatric patients were included, as were articles discussing both pediatric and adult patients, if data on individual pediatric patients were available.Inclusion criteria were met by 122 total reports discussing 1032 patients. Reports consisted of 2 randomized controlled trials, 4 prospective comparative cohorts, 83 case series, 2 case-control studies, and 31 case reports. Included articles assessed the use of aloe, apremilast, anthralin, anti-interferon gamma antibodies, botulinum toxin, corticosteroids, contact immunotherapies, cryotherapy, hydroxychloroquine, hypnotherapy, imiquimod, Janus kinase inhibitors, laser and light therapy, methotrexate, minoxidil, phototherapy, psychotherapy, prostaglandin analogs, sulfasalazine, topical calcineurin inhibitors, topical nitrogen mustard, and ustekinumab.English-only articles with full texts were used. Manuscripts with adult and pediatric data were only incorporated if individual-level data for pediatric patients were provided. No meta-analysis was performed.Topical corticosteroids are the preferred first-line treatment for pediatric AA, as they hold the highest level of evidence, followed by contact immunotherapy. More clinical trials and comparative studies are needed to further guide management of pediatric AA and to promote the potential use of pre-existing, low-cost, and novel therapies, including Janus kinase inhibitors.
Carotid artery disease remains a major etiology of ischemic stroke. As data emerges demonstrating the safety and efficacy of carotid artery stenting, the importance of determining patency of carotid stents over time increases. Given alterations in the architecture and compliance of the carotid artery after a stent is deployed, subtleties in the performance and interpretation of carotid duplex ultrasonography must be appreciated. This section describes these factors in detail, and provides optimal methods to interpret these examinations.
Radiation-induced intracranial vasculopathy is a rare complication following treatment of intracranial tumors. We treated a 49-year-old woman presenting with severe middle cerebral artery stenosis 14 years post-radiotherapy. As more patients are treated successfully with radiation therapy for intracranial neoplasm, stenotic cerebrovascular disease may become a more common etiology for ischemic infarction in this patient population.
Carotid revascularization procedures for the prevention of acute ischemic stroke have a low but definite risk of intracerebral hemorrhage (ICH). After carotid endarterectomy (CEA) the risk is less than 1%, and accumulating data on the newer carotid angioplasty and stenting (CAS) procedure suggest a similar risk. A probably more common and underdiagnosed complication of CEA and CAS is the so-called “hyperperfusion” syndrome. A post-revascularization increase in cerebral blood flow (CBF) in the ipsilateral hemisphere is thought to underlie the pathophysiology of the syndrome. The increased unilateral hemispheric CBF leads to vasogenic edema due to re-perfusion of maximally dilated capillaries which have lost their autoregulatory capacity as a result of chronic ischemia. The clinical features of severe post-procedural hypertension followed by headache, focal neurological deficits, and seizures has an imaging correlate of unilateral hemispheric vasogenic edema in the absence of MRI features of infarction. In the absence of associated ICH, the symptoms often improve over a period of days after aggressive control of hypertension. The key to the prevention of the hyperperfusion syndrome and post-carotid revascularization ICH is close monitoring of peri-procedural blood pressure, and aggressive treatment of hypertension.
This article will describe in detail the unique mechanism of stroke in congenital heart disease through paradoxical embolism. The emphasis will be on the influence of hemodynamics of the different types of anomalies on the likelihood of stroke, starting with the high-risk patients with cyanotic congenital heart disease, then the moderate-risk patients with repaired or palliated conditions, the relatively small risk of congenital anomalies with mainly left-to-right shunts, and finally, the very unusual but interesting association of patent foramen ovale with stroke in otherwise normal hearts. Conditions that enhance the formation of potential emboli will be discussed shortly. Two conditions with alleged association to stroke, secondary erythrocythemia and mitral valve prolapse, will be reviewed critically, to claim a lack of a clear association. Stroke and aortic coarctation will be discussed. Other cardiac causes of stroke in patients with congenital heart disease that are not unique to this group will not be covered in this article.
Intracerebral hemorrhage (ICH) and some of its associated features are accompanied by increased levels of certain biochemical markers in serum. The amount of peri-hematoma edema formation is correlated with serum levels of glutamate, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and intercellular adhesion molecule-1 (ICAM-1). In addition, serum glutamate levels are associated with poor neurological outcome. The matrix metalloproteinases (MMPs) are elevated in serum in patients with ICH. The MMP-9 isoform is also correlated with the initial volume of peri-hematoma edema, its subsequent enlargement in the first 48 hours from ICH onset, and neurological worsening. Hematoma enlargement after ICH onset is correlated with high serum levels of IL-6, TNF-α, MMP-9, and cellular fibronectin (c-Fn). The risk of hemorrhagic complications after acute ischemic stroke treated with t-PA thrombolysis is increased in subjects with elevated baseline serum levels of MMP-9. The above observations suggest that the determination of a number of serum markers may become an important tool for the prediction of ICH outcome, as well as for the assessment of risk of bleeding after thrombolysis for acute ischemic stroke.
Intracerebral hemorrhage (ICH) has an incidence of 10-20/100,000. Its most important risk factors are age, gender, race (more common in African-American, Hispanic, and Asian populations), hypertension, excessive alcohol use, and smoking. The latter two underline the importance of prevention via modification of behavior, while the value of treatment of hypertension is highlighted by clinical trial data (Perindopril Protection Against Recurrent Stroke Study [PROGRESS]) indicative of substantial risk reduction (50% relative risk reduction) by relatively modest lowering of blood pressure (by 9/4 mmHg). The importance of genetic factors for ICH has been recently documented, with endoglin gene insertions and Factor XIII polymorphisms being associated with a significant increase in the risk of ICH. The prognosis of ICH is dependent on age, level of consciousness, hematoma volume, and intraventricular extension of hemorrhage, which are all predictors of mortality. The risk of ICH recurrence is about 2%/year overall, but with an increase to 4-5%/year if the localization is lobar. Predictors of ICH recurrence include age > 65, carrying the ϵ2 and ϵ4 alleles of the apolipoprotein E gene, the presence of asymptomatic microhemorrhages and leukoaraiosis. The functional outcome of ICH is poor, with only 12% of survivors being independent at 30 days.
An elderly man with multiple hemorrhagic, presumed neoplastic lesions of the brain is described who could not undergo magnetic resonance imaging because of a pacemaker. On autopsy, metastatic melanoma was identified. In this report, we discuss the differential diagnosis of hemorrhagic metastases, the incidence and prognosis of metastatic melanoma to the brain, and the limited therapeutic options for metastatic melanoma.
Cerebrovascular disease, in particular stroke, is a common complication in cancer patients, secondary in incidence only to brain metastases. Autopsy studies suggest that a substantial proportion of strokes in these patients is overlooked in the clinical setting. In general, the clinical presentation of stroke in cancer patients and in nononcologic patients is similar. Embolic focal cerebral ischemia is the most frequent type of stroke with a reported ratio of approximately 55%, which is substantially lower than the ratio of approximately 80% in the general population. The underlying malignancy influences the proportion of embolic versus hemorrhagic stroke. The most common cause of stroke in cancer patients is nonbacterial thrombotic endocarditis (NBTE), a noninfectious type of endocarditis characterized by sterile fibrin vegetations. Other common causes, in the order of frequency, include tumor-induced coagulopathy, atherosclerosis, modification of blood viscosity, and therapy-induced stroke. There is no general agreement whether cancer is an independent risk factor for stroke such as traditional risk factors like hypertension or smoking. The challenge to the clinician is to elaborate whether the stroke is specifically related to cancer or whether it is due to vascular comorbidity like in the general population. The treatment of stroke in cancer patients is usually similar to the treatment of stroke in the general population, except for the treatment of the underlying malignancy if applicable.
Transcranial Doppler (TCD) is currently used in monitoring subarachnoid hemorrhage, acute stroke, and carotid endarterectomy and in diagnosing intracranial vascular disease. In this article we review other uses of TCD, in systemic conditions related to ischemic stroke. Transcranial Doppler, in fact, can identify right-to-left shunts (RLS), usually due to patent foramen ovale (PFO), a risk factor for cryptogenic stroke in the young. Recently an association between RLS and migraine with aura has been reported; migraine is a risk factor for stroke, for silent brain infarctions, and for silent white matter disease, but there are no data yet on a similar risk for the association of migraine plus PFO. TCD can also be used to stratify the risk of stroke in children with sickle cell disease, to better identify subjects to be transfused to prevent strokes.
Immune mediated systemic disorders may involve the cerebral blood vessels and cause brain ischemia or hemorrhage. Pertinent causes of stroke associated with immune disorders include cardioembolism due to direct involvement of the heart and its valves by the underlying disorder, vasculopathy and a hypercoagulable state related to the primary disorder, frank vasculitis of the cerebral blood vessels, and an increased rate of atherosclerotic changes in the cerebral vasculature secondary to other organ involvement by the primary disease process. It is extremely important to define the exact pathology involved as treatment options vary. Despite the fact that brain involvement is associated with unfavorable prognosis in many of these disorders, prevention of further cerebrovascular events is a feasible goal in most. Furthermore, specific therapy aimed at the cause of the disease (eg, immunosuppressive therapy in giant cell arteritis) results in greatly improved survival rates in certain disorders.
Intracerebral hemorrhage (ICH) has been traditionally imaged with computerized tomography (CT), which allows an immediate distinction between ICH and ischemia as the mechanism of an acute stroke. In recent years, the refining of several techniques of magnetic resonance (MR) imaging has allowed a more precise characterization of the anatomy of ICH, its associated events (such as surrounding edema), and its time-course. The latter has been facilitated by an understanding of the various biochemical changes that take place in and around the hematoma, and which correlate with the temporal course of the evolution of the ICH. In addition, the measurement of the susceptibility effect by MR imaging has permitted the identification of small asymptomatic microhemorrhages, which are potentially important predictors of ICH recurrence, as well as risk factors for ICH due to anticoagulant and thrombolytic treatment.
We will review cerebrovascular complications of infectious diseases of the CNS. The emphasis will be on common infections causing stroke, including pyogenic meningitis, infective endocarditis, tuberculosis, leptospirosis, syphilis, as well as fungal and parasitic diseases. Most of these conditions cause stroke through a mechanism of angiitis, which is an inflammation of the vessel wall induced by the presence of microorganisms within the CNS. A stroke may occur as the primary or sole manifestation of the infectious disease or may present in the setting of a diffuse encephalopathy. Infection-related strokes may be ischemic or hemorrhagic and range in severity from asymptomatic to fatal. Precise knowledge of the spectrum of these conditions is important to direct prompt therapy to reduce the risk of further vascular damage.
A 53-year-old woman with a prosthetic heart valve developed a left occipital intracerebral hemorrhage (ICH) while on treatment with warfarin for thromboembolism prophylaxis. The international normalized ratio was 5.8. She presented with left occipital headache, right homonymous hemianopia, and fluent aphasia. The ICH expanded in the initial hours after onset but subsequently stabilized after treatment with vitamin K1, fresh frozen plasma, and recombinant activated factor VII. Her hospital course was stable, and the clinical deficits gradually resolved (aphasia) or improved (right homonymous hemianopia) after hospital discharge. She had the warfarin treatment restarted after 8 days from ICH onset, without subsequent complications. The available data and recommendations on the issue of restarting warfarin anticoagulation after an episode of intracranial bleeding are reviewed.
Transient isolated brainstem symptoms (eg, isolated vertigo, dysarthria, diplopia) are not consistently classified as transient ischaemic attacks (TIAs) and data for prognosis are limited. If some of these transient neurological attacks (TNAs) are due to vertebrobasilar ischaemia, then they should be common during the days and weeks preceding posterior circulation strokes. We aimed to assess the frequency of TNAs before vertebrobasilar ischaemic stroke.We studied all potential ischaemic events during the 90 days preceding an ischaemic stroke in patients ascertained within a prospective, population-based incidence study in Oxfordshire, UK (Oxford Vascular Study; 2002–2010) and compared rates of TNA preceding vertebrobasilar stroke versus carotid stroke. We classified the brainstem symptoms isolated vertigo, vertigo with non-focal symptoms, isolated double vision, transient generalised weakness, and binocular visual disturbance as TNAs in the vertebrobasilar territory; atypical amaurosis fugax and limb-shaking as TNAs in the carotid territory; and isolated slurred speech, migraine variants, transient confusion, and hemisensory tingling symptoms as TNAs in uncertain territory.Of the 1141 patients with ischaemic stroke, vascular territory was categorisable in 1034 (91%) cases, with 275 vertebrobasilar strokes and 759 carotid strokes. Isolated brainstem TNAs were more frequent before a vertebrobasilar stroke (45 of 275 events) than before a carotid stroke (10 of 759; OR 14·7, 95% CI 7·3–29·5, p<0·0001), particularly during the preceding 2 days (22 of 252 before a vertebrobasilar stroke vs two of 751 before a carotid stroke, OR 35·8, 8·4–153·5, p<0·0001). Of all 59 TNAs preceding (median 4 days, IQR 1–30) vertebrobasilar stroke, only five (8%) fulfilled the National Institute of Neurological Disorders and Stroke (NINDS) criteria for TIA. The other 54 cases were isolated vertigo (n=23), non-NINDS binocular visual disturbance (n=9), vertigo with other non-focal symptoms (n=10), isolated slurred speech, hemisensory tingling, or diplopia (n=8), and non-focal events (n=4). Only 10 (22%) of the 45 patients with isolated brainstem TNAs sought medical attention before the stroke and a vascular cause was suspected by their physician in only one of these cases.In patients with definite vertebrobasilar stroke, preceding transient isolated brainstem symptoms are common, but most symptoms do not satisfy traditional definitions of TIA. More studies of the prognosis of transient isolated brainstem symptoms are required.Wellcome Trust, UK Medical Research Council, Dunhill Medical Trust, Stroke Association, National Institute for Health Research (NIHR), Thames Valley Primary Care Research Partnership, and the NIHR Biomedical Research Centre, Oxford.
Ultrasound perfusion imaging of the cerebral microcirculation is a new semi-invasive bedside technique to evaluate human brain perfusion. Several approaches have been evaluated for the qualitative assessment of brain perfusion in healthy subjects and in patients suffering from acute ischemic stroke. The analysis of ultrasound contrast agent bolus kinetics yields various time-intensity curve parameters that qualitatively describe regional brain perfusion. In healthy subjects, there is a close correlation between the time to peak intensity measurements as performed by perfusion ultrasound and perfusion-weighted MRI. In the acute phase of ischemic stroke, the peak signal increase is the most useful curve parameter to predict the area of definite infarction. Ultrasound perfusion imaging performed in the early phase can predict the outcome of the individual stroke patient. Diminution and Replenishment kinetics are new modalities for the visualization of brain perfusion, the latter being more promising because of the fast imaging time resulting in a lower vulnerability to movement artifacts. The different approaches will have to be compared regarding their ability to provide valid thresholds for differentiation between normal and abnormal perfusion in the acute stroke situation. At present, the foremost limitations of transcranial ultrasound perfusion imaging are attenuation phenomena, caused by the temporal bone, which might be overcome by new imaging systems that are currently under development.
High-resolution ultrasound images of the carotid artery wall can be used to identify early changes associated with atherosclerosis. The precision of the intima-media thickness (IMT) measurement is dependent on the sonographer, the imaging device and the analysis software. When done under tight quality control, IMT measurements can identify individuals at risk for future cerebrovascular events starting at an earlier age than what is possible with other diagnostic tests.
Stroke is a heterogeneous syndrome caused by multiple etiologies. Heritable defects in connective tissue cause a small fraction of ischemic and hemorrhagic stroke. They are the consequence of mutations in genes encoding extracellular matrix constituents such as collagens and proteoglycans. Ehlers–Danlos syndrome, Marfan’s syndrome, osteogenesis imperfecta, and pseudoxantoma elasticum are the most common disorders responsible for cerebrovascular manifestations. Neurofibromatosis and polycystic kidney disease, although not connective tissue disorders, are hereditary diseases with a high prevalence of vascular complications. Ehlers–Danlos syndrome type IV is the most frequent and most life-threatening form due to the presence of intracranial aneurysms, carotid-cavernous fistulas, and arterial dissections. Marfan’s syndrome has a typical phenotype associated with arterial dissections and intracranial aneurysms. Osteogenesis imperfecta, although infrequent, can present with aneurysms, dissections, fistulas, and stenosis of cerebral vessels. Pseudoxanthoma elasticum is commonly associated with occlusive disease of small vessels and other complications such as aneurysms or arteriovenous malformations. Autosomal–dominant polycystic kidney disease is a common cause of multiple intracranial aneurysms. Neurofibromatosis type 1 is characterized by multiple neurofibromas; it is responsible for stenosis or occlusions of intracranial arteries and vascular malformations. These vasculopathies are associated with a relatively high prevalence of cerebrovascular disease; their early recognition should help in the investigation of asymptomatic carriers, and to provide genetic counseling. The growing knowledge of molecular biology could help in the understanding of the underlying mechanism of these complex disorders as well as identify future therapeutic interventions.
