Cranial Ischemic Complications Research Articles

Age, anticoagulants, hypertension and cardiovascular genetic traits predict cranial ischaemic complications in patients with giant cell arteritis

ObjectivesThis project aimed to determine whether cranial ischaemic complications at the presentation of giant cell arteritis (GCA) were associated with pre-existing cardiovascular (CV) risk factors, CV disease or genetic risk...

Age at diagnosis influences the clinical phenotype, treatment strategies and outcomes in patients with giant cell arteritis: results from the observational GCAGE study on a large cohort of 1004 patients

BackgroundImmune and vascular ageing are proposed risk factors for giant cell arteritis (GCA). Data on the impact of age at diagnosis of GCA on the clinical presentation and course of...

Evidence-based Role of Aspirin in Giant Cell Arteritis: A Literature Review.

Giant cell arteritis (GCA), or temporal arteritis, is a medium to large vessel vasculitis seen in the elderly. Its presentation varies from fever of unknown origin to cranial ischemic complications including complete vision loss. The early initiation of steroids is key to preventing complications of GCA. Here we discuss the role of aspirin in the treatment of GCA, both as an antithrombotic agent and its increasingly utilized anti-inflammatory properties. The aim of this review article is to examine the evidence behind the use of aspirin as an adjunct to steroids for the prevention of cranial ischemic complications.

Risk factors for severe cranial ischaemic complications in giant cell arteritis.

Vision complications and a stroke represent severe cranial ischaemic complications (sCIC) associated with increased morbidity and mortality in GCA. We aimed to determine the risk factors for sCIC in GCA. We analysed the medical records of prospectively enrolled GCA patients diagnosed between September 2011 and August 2019, and compared the clinical and laboratory characteristics of patients with and without sCIC defined as either severe vision complications (diplopia, transient vision loss, permanent partial vision field/acuity defect and permanent visual loss) or stroke. During the 96-month observation period, we identified 295 new GCA patients [65.4% female, median (interquartile range) age 74.7 (67.3-80.0) years]. Sixty-one (20.7%) patients developed sCIC (52 isolated severe vision complications, 5 isolated ischaemic strokes and 4 patients with both complications). In a multivariable logistic regression model jaw claudication [odds ratio (OR) 3.43 (95% CI: 1.84, 6.42), P < 0.001], smoking [OR 1.92 (95% CI: 1.01, 3.65), P = 0.046] and increasing age [OR 1.08 (95% CI: 1.04, 1.13), P < 0.001] were significantly associated with sCIC. Higher CRP [OR 0.99 (0.99-1.00), P = 0.011] decreased the risk of sCIC. When considered separately, the odds for severe vision complications increased with age and jaw claudication, and decreased with polymyalgia rheumatica, constitutional symptoms and higher CRP. Atrial fibrillation emerged as the sole independent predictor of ischaemic stroke. Increasing age, jaw claudication and smoking predicted sCIC, while higher CRP decreased the risk of sCIC in our GCA cohort.

Interleukin 12 and interleukin 23 play key pathogenic roles in inflammatory and proliferative pathways in giant cell arteritis

ObjectivesThe pathogenesis of giant cell arteritis (GCA) remains unclear. TH1 and TH17 pathways are implicated, but the proximal initiators and effector cytokines are unknown. Our aim was to assess the...

Visual loss and other cranial ischaemic complications in giant cell arteritis.

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals aged 50 years and over. GCA typically affects large and medium-sized arteries, with a predilection for the extracranial branches of the carotid artery. Patients with GCA usually present with symptoms and signs that are directly related to the artery that is affected, with or without constitutional manifestations. The most dreaded complication of GCA is visual loss, which affects about one in six patients and is typically caused by arteritis of the ophthalmic branches of the internal carotid artery. Before the advent of glucocorticoid treatment, the prevalence of visual complications was high. Increasing awareness by physicians of the symptoms of GCA and advances in diagnostic techniques over the past twenty years have also contributed to a substantial decline in the frequency of permanent visual loss. Ischaemic brain lesions are less common than visual lesions, and mostly result from vasculitis of the extradural vertebral or carotid arteries. In the case of both the eye and the brain, ischaemic damage is thought to result from arterial stenosis or occlusion that occurs secondary to the inflammatory process. The inflammatory response at the onset of arteritis, its role as a predictor of complications and the role of traditional cardiovascular risk factors have been extensively investigated in the past decade. In this Review, the epidemiology, risk factors, clinical presentation and current therapeutic approach of GCA-related ischaemic events are discussed, with a particular emphasis on visual loss.

Giant Cell Arteritis in Mexican Patients

Giant cell arteritis (GCA) is the most common primary systemic vasculitis worldwide, although it seems to be very rare in some areas, such as Latin America. The objective of the study was to describe the clinical, laboratory, and treatment features in a Mexican Mestizo population with GCA. Retrospective data chart review (1989-2010). Twenty-two patients with GCA were identified, 18 women and 4 men. Mean age was 73 (SD, 7.9) years. Diagnosis was made at a mean of 67 (SD, 83.6) days from symptom onset. Most frequent presenting symptoms included headache (90%), constitutional symptoms (86%), and polymyalgia rheumatica (59%). Severe cranial ischemic complications were present in 32%. Amaurosis fugax and blindness were present in 36% and 27%, respectively. High erythrocyte sedimentation rate was present in 89% of patients. Rapid response to prednisone treatment was seen, but in 10 patients, relapse occurred, possibly related to fast tapering. Additional treatment was methotrexate (n = 8), azathioprine (n = 5), and cyclophosphamide (n = 3). Median follow-up was 242 (SD, 214) weeks. Giant cell arteritis is rarely recognized in Latin America. We report on characteristics of GCA in a population of Mexican Mestizos, as ours is the largest series to be reported from Latin America so far. When compared with other series, age at onset is similar, females are more affected, and although a good response to corticosteroid treatment was seen, a higher frequency of amaurosis fugax and blindness was observed, accounting for an unfavorable functional outcome in 6 (27%) of 22 patients.

Improving therapeutic options for patients with giant cell arteritis

Glucocorticoids remain the mainstay of treatment of giant cell arteritis. The aim of this review is to establish the optimal schedule of glucocorticoid administration, and to ascertain which other treatments may be used as glucocorticoid-sparing agents. An initial dose of 40-60 mg/day of prednisone is usually adequate. Patients at risk of developing ischemic complications require dosages of around 1 mg/kg/day, whereas pulse glucocorticoid therapy is no more effective in preventing ischemic complications. In patients with longstanding disease or those at risk for glucocorticoid-related adverse events, methotrexate or azathioprine can be used as glucocorticoid-sparing drugs. Infliximab has been demonstrated to be efficacious in glucocorticoid-resistant disease in an open study, whereas a randomized controlled trial showed no efficacy in patients with recent-onset disease. Finally, two retrospective studies suggest that low-dose aspirin may decrease the rate of cranial ischemic complications secondary to giant cell arteritis. Glucocorticoids remain the cornerstone of therapy for giant cell arteritis. To achieve maximal efficacy but minimize glucocorticoid-related adverse reactions, dosage should be individually tailored. In patients with longstanding, recalcitrant disease, methotrexate, azathioprine or tumor necrosis factor-alpha inhibitors may be considered. Aspirin is recommended in all patients unless contraindicated. Osteoporosis prophylaxis should also be regularly implemented.

An elderly lady with a painful swollen face

Giant cell arteritis (GCA) is the most common vasculitis in the elderly. Common presenting symptoms include cranial ischemic complications, constitutional manifestations and polymyalgia rheumatica. Facial and cervical edema is increasingly recognized as an inaugural sign of GCA. We present a case with tender facial and cervical edema as the dominating symptom.

PlA1/A2 polymorphism of the platelet glycoprotein receptor IIIA and risk of cranial ischemic complications in giant cell arteritis

To investigate potential associations of the PlA1/A2 polymorphism of the platelet glycoprotein IIIa (GPIIIa) gene with susceptibility to, and clinical expression of, giant cell arteritis (GCA). One hundred forty patients with biopsy-proven GCA who were residents of Reggio Emilia, Italy, and 241 population-based healthy controls from the same geographic area were genotyped for the PlA1/A2 polymorphism of the platelet GPIIIa gene by molecular methods. The patients were divided into subgroups according to the presence or absence of polymyalgia rheumatica and cranial ischemic complications. The distribution of the PlA1/A2 genotype was investigated, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. The distribution of the PlA1/A2 genotype differed significantly between GCA patients with and those without visual loss caused by anterior ischemic optic neuritis (P = 0.016, corrected P [P(corr)] = 0.048). The PlA2 allele was found significantly more frequently in GCA patients with anterior ischemic optic neuritis than in those without anterior ischemic optic neuritis (P = 0.023, P(corr) = 0.046, OR 2.4 [95% CI 1.2-4.8]). Homozygosity for the PlA2 allele was significantly more frequent among GCA patients with anterior ischemic optic neuritis than among those without (P = 0.019, P(corr) = 0.038, OR 7.1 [95% CI 1.64-30.6]). Cranial ischemic complications occurred in 8 of 19 patients (42.1%) receiving antiplatelet therapy, compared with 22 of 118 patients (18.6%) not receiving such therapy (P = 0.03, OR 3.2 [95% CI 1.1-8.8]). Our findings show that A2/A2 homozygosity is associated with an increased risk of visual loss due to anterior ischemic optic neuritis in GCA patients. Antiplatelet therapy, however, was not effective in reducing the risk of ischemic events in this population of GCA patients.

Are steroids alone sufficient for the treatment of giant cell arteritis?

Glucocorticosteroids are the cornerstone of treatment of giant cell arteritis. An initial dose of prednisone or its equivalent of at least 40-60mg per day as single or divided dose is usually adequate. Glucocorticosteroids may prevent, but usually do not reverse, visual loss. A treatment course of 1-2 years is often required. Some patients, however, have a more chronic-relapsing course and may require low doses of glucocorticosteroids for several years. Glucocorticosteroid-related adverse events are common. In studies on immunosuppressant agents, methotrexate has been used as a glucocorticosteroid-sparing drug with conflicting results. This drug may, however, be given to patients who need high doses of glucocorticosteroids to control active disease and who have serious side effects. A recent pilot study found that infliximab was efficacious in patients with glucocorticosteroid-resistant giant cell arteritis. However, randomized controlled trials are required to define the role of anti-tumor necrosis factor-alpha agents in the treatment of giant cell arteritis. Finally, low-dose aspirin has been shown in a recent retrospective study to decrease the rate of cranial ischemic complications secondary to giant cell arteritis. It is conceivable that the definition of different patterns of inflammation in giant cell arteritis in the future might facilitate the design of differentiated therapeutic approaches.

Treatment with statins does not exhibit a clinically relevant corticosteroid-sparing effect in patients with giant cell arteritis.

Introduction Giant cell arteritis (GCA) is a chronic granulomatous vasculitis preferentially targeting largeand medium-sized vessels in aged people. The inflammatory lesions eventually lead to vessel occlusion and 15% of patients develop cranial ischemic complications, particularly visual loss (1,2). The granulomatous nature of GCA lesions, with the frequent presence of multinucleated giant cells, has classically suggested a delayed-type hypersensitivity reaction but the potential triggering agents remain unknown (1–3). CD4 T cells infiltrating the vessel wall display a T helper type 1 functional differentiation with copious production of interferon (IFN ), a major cytokine in macrophage activation (3). Activated macrophages produce angiogenic factors and proinflammatory cytokines, such as interleukin-1 , tumor necrosis factor , and interleukin-6 (IL-6) (2,3). These mediators amplify the inflammatory response by inducing endothelial cell adhesion molecules for leukocytes and chemokines, and by generating new vessels through which additional leukocytes may subsequently invade the vessel wall (2,4–7). Macrophages also participate in tissue destruction by producing oxidative damage and secreting metalloproteases, and in tissue repair by secreting fibrogenic cytokines that eventually may lead to vessel occlusion with its ensuing ischemic complications (3). Corticosteroids are, at present, the treatment of choice for patients with GCA (1–3). Although their ability to modify the course of the disease or to cure it is questionable, corticosteroids induce dramatic functional changes in GCA lesions both in humans and in human arteritis– severe combined immunodeficient mouse chimeras (4,8,9). These functional changes result in a rapid relief of symptoms and prevention of ischemic complications. However, therapeutic requirements are highly variable among patients. Some patients achieve persistent remission of the disease within a few months, whereas others present recurrent relapses and need maintenance doses of corticosteroids for long periods of time. Sustained corticosteroid therapy has been associated with the development of dyslipidemia by inducing insulin resistance, increasing the hepatic synthesis of very lowdensity lipoproteins and triglyceride, enhancing the activity of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, and inhibiting lipoprotein lipase. Moreover, studies in vitro have demonstrated that corticosteroids inhibit the activity of the low-density lipoprotein (LDL) receptor leading to an increase in LDL levels in patients (10–13). For that reason, some patients diagnosed with GCA receiving corticosteroid therapy may require lipidlowering agents during their followup. HMG-CoA reductase inhibitors, statins, are widely and effectively used as hypolipidemic agents. They competitively inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. Treatment with statins results in a reduction of the cholesterol levels through a decrease in cholesterol synthesis and by increasing the expression of hepatic LDL receptors, which clear LDL and LDL precursors from the bloodstream (14). Numerous clinical trials have demonstrated that statins reduce coronary heart disease mortality and the incidence of cardiovascular events (14–16). Recently, it has been demonstrated that statins also have antiinflammatory properties, through various mechanisms (14). The effect of statins on the inflammatory component of atherosclerosis is considered to be an important mechanism through which statins reduce cardiovascular events and death (14,17,18). Furthermore, statins have demonstrated to be of therapeutic benefit in animal models of chronic inflammatory conditions (19– 21) and have been shown to reduce graft rejection in heart Supported by Ministerio de Ciencia y Tecnologia and Fondo Europeo de Desarrollo Regional (FEDER; SAF 0203307) and Generalitat de Catalunya (2001/SGR/00379). Dr. Garcia-Martinez was supported by a research award from Hospital Clinic. Dr. Cid was supported by a research award from IDIBAPS. Ana Garcia-Martinez, MD, Jose Hernandez-Rodriguez, MD, Josep M. Grau, MD, Maria C. Cid, MD: Hospital Clinic, University of Barcelona, Barcelona, Spain. Address correspondence to Maria C. Cid, MD, Department of Internal Medicine, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain. E-mail: mccid@clinic.ub.es. Submitted for publication June 18, 2003; accepted in revised form December 16, 2003. Arthritis & Rheumatism (Arthritis Care & Research) Vol. 51, No. 4, August 15, 2004, pp 674–678 DOI 10.1002/art.20541 © 2004, American College of Rheumatology

Low‐dose aspirin and prevention of cranial ischemic complications in giant cell arteritis

Cranial ischemic complications such as cerebrovascular accidents (CVAs) and acute visual loss are among the leading causes of giant cell arteritis (GCA)-related morbidity. In this retrospective study, we evaluated the effect of treatment with low-dose aspirin on the incidence of cranial ischemic complications in GCA. Charts of 175 consecutive patients in whom GCA was diagnosed between 1980 and 2000 were reviewed for medical data. Data for 166 patients who were followed up for at least 3 months were also available. At the time of the diagnosis of GCA, 36 patients (21%) had already been receiving low-dose aspirin (100 mg/day). In all cases, the indication for this treatment was ischemic heart disease. There were no significant differences between the aspirin-treated and non-aspirin-treated groups regarding the mean age of patients, the male-to-female ratio, duration of GCA-related symptoms, rates of headaches, systemic symptoms, and jaw claudication, and the mean erythrocyte sedimentation rate, hemoglobin count, and platelet count. Cerebrovascular risk factors (hypertension, hyperlipidemia, or diabetes mellitus) were more common in the aspirin-treated group (38.9% versus 20%; P= 0.03). Cranial ischemic complications were diagnosed in 43 patients at presentation: 30 patients had acute visual loss, 11 had CVAs, and 2 had both conditions simultaneously. Only 3 of the aspirin-treated patients (8%) presented with cranial ischemic complications, compared with 40 (29%) of the non-aspirin-treated patients (P = 0.01). Despite the use of steroid therapy, cranial ischemic complications developed in 14 of the 166 patients followed up for 3 months or longer. However, cranial ischemic complications developed in only 3% of the aspirin-treated patients, compared with 13% of the patients treated with prednisone only (P = 0.02). These data suggest that low-dose aspirin decreases the rate of visual loss and CVAs in patients with GCA.

Risk factors for cranial ischemic complications in giant cell arteritis.

Cranial ischemic complications (CICs) are among the presenting manifestations of giant cell arteritis (GCA). Yet patients with GCA may develop CICs at a later stage, despite steroid therapy. In the current report we delineate risk factors for CICs, both at presentation and during follow-up, and review the relevant literature. We reviewed charts of 175 patients with GCA. Follow-up data were available for 166 patients. CICs at presentation or developing within 2 weeks of GCA diagnosis were considered GCA related. CICs developing later were considered GCA related only when associated with other GCA-related manifestations or acute-phase reactions. Associations between CICs and other variables were tested by multivariate analysis. At presentation, 43 patients (24.6%) had CICs. Risk factors were transient cerebro-ophthalmic ischemic episodes (COIEs) (odds ratio [OR] 4.3) and male sex (OR 2.5), while the presence of systemic symptoms was "protective" (OR 0.3). During follow-up 8.4% of patients with GCA developed new CICs. Risk factors in these cases were previous CICs at presentation (OR 5.6) and transient COIEs developing during follow-up (OR 14.8). The use of low-dose aspirin was protective (OR 0.2). These data, together with data from the literature review, suggest that GCA patients with transient COIEs and without fever or other systemic symptoms are at increased risk of presenting with CICs. Risk factors for late-developing CICs were CICs at presentation and late-developing transient COIEs.

Facteurs prédictifs de complications céphaliques ischémiques irréversibles au cours de la maladie de Horton : étude prospective sur 178 patients

Purpose. – To search for risk factors of developing irreversible cranial ischemic complications (ICIC) in patients with giant cell arteritis (GCA) and to explore whether two subsets of patients (high risk and low risk of developing ICIC) can be defined. Methods. – One-hundred seventy-eight consecutive patients with temporal arteritis (149 biopsy-proven) were diagnosed and followed up in a department of Internal Medicine between 1976 and 1999. The patients were separated into two groups, according to the presence or absence of ICIC, with comparison of 17 clinical and biological parameters prospectively recorded for each patient using a pre-established comprehensive questionnaire. Results. – ICIC occurred in 25 patients (14%), with amaurosis in 22 cases. Suggestive symptoms and/or signs of temporal arteritis were present in 92% of the patients, lasting 50 days (median) before the onset of ICIC. Forty-three patients (24%) complained of transient visual ischemic symptoms (TVIS), which preceded acute blindness in 11 cases. A multivariate logistic regression, from which 28 cases with upper limb artery involvement were excluded for technical reasons (no CCII in any case, thus predicting perfectly the lack of ischemic risk, P = 0.02), indicated that the only independent variables associated with the ischemic risk were: a history of TVIS ( P = 0.05), the lack of signs of polymyalgia rheumatica (PMR; P = 0.02), lower blood levels of fibrinogen ( P = 0.024) and higher mean blood platelets levels ( P = 0.006). However, these five variables predicted only 30% of the variability of the model. Sensitivity, specificity, positive and negative predictive values of the model reached respectively 36, 96, 64 and 88%. Overall, 86% of the cases were correctly classified with respect to the ischemic risk. Conclusion. – The rate of ICIC should be reduced by an earlier recognition of the usual signs of temporal arteritis. Several independent risk factors of ICIC have been identified. However, the logistic model failed to predict accurately the ischemic risk in 14% of the cases, indicating that as yet unrecognised factors probably exist that play a role in the occurrence of ICIC. Nevertheless, regarding the strong association between platelet levels and ICIC, patients with thrombocytosis should receive initially both corticosteroids and antiplatelet agents.

Visual Complications Are Still Frequent in Giant Cell Arteritis

Cranial ischemic complications -- especially permanent visual loss -- are not uncommon in patients with giant cell arteritis (GCA). To investigate the

Visual manifestations of giant cell arteritis. Trends and clinical spectrum in 161 patients.

Giant cell (temporal) arteritis (GCA) is the most common systemic vasculitis in Western countries. It involves large and medium-sized vessels with predisposition to the cranial arteries in the elderly. Cranial ischemic complications, in particular permanent visual loss, constitute the most feared aspects of this vasculitis. Although the use of corticosteroids and a higher physician awareness may have contributed to a decrease in the frequency of severe ischemic complications, permanent visual loss is still present in 7%-14% of patients. To investigate further the incidence, trends, and clinical spectrum of visual manifestations in patients with GCA, we examined the features of patients with biopsy-proven GCA diagnosed at the single reference hospital for a defined population in northwestern Spain during an 18-year period. Predictive factors for the development of any visual manifestation, not only permanent visual loss, were also examined. Between 1981 and 1998, 161 patients were diagnosed with biopsy-proven GCA. Visual ischemic complications were observed in 42 (26.1%), and irreversible blindness, mainly due to anterior ischemic optic neuropathy and frequently preceded by amaurosis fugax, was found in 24 (14.9%). Despite a progressive increase in the number of new cases diagnosed, there was not a significant change in the proportion of patients with visual manifestations during the study period (p = 0.37). Patients with visual ischemic complications had lower clinical and laboratory biologic markers of inflammation. Indeed, during the last years of the study, anemia was associated with a very low risk of visual complications. Also, HLA-DRB1*04-positive patients had visual manifestations more commonly. Patients with other ischemic complications developed irreversible blindness more frequently. The best predictors of any visual complication were HLA-DRB1*04 phenotype (odds ratio [OR] 7.47) and the absence of anemia at the time of admission (OR for patients with anemia = 0.07). The best predictors of irreversible blindness (permanent visual loss) were amaurosis fugax (OR 12.63) and cerebrovascular accidents (OR 26.51). The present study supports the claim that ocular ischemic complications are still frequent in biopsy-proven GCA patients from southern Europe. The presence of other ischemic complications constitutes an alarm for the development of irreversible blindness. In contrast, a higher inflammatory response may be a protective factor against the development of cranial ischemic events.

No association between the inflammatory response and the risk of developing irreversible cranial ischemic complications: Comment on the article by Cid et al

No association between the inflammatory response and the risk of developing irreversible cranial ischemic complications: Comment on the article by Cid et al

No association between the inflammatory response and the risk of developing irreversible cranial ischemic complications: Comment on the article by Cid et al

No association between the inflammatory response and the risk of developing irreversible cranial ischemic complications: Comment on the article by Cid et al

Association between strong inflammatory response and low risk of developing visual loss and other cranial ischemic complications in giant cell (temporal) arteritis.

To identify clinical and biochemical parameters that have good predictive value for identifying giant cell (temporal) arteritis (GCA) patients who are at high or low risk of developing cranial ischemic events. In this multicenter study, records of patients at 3 university hospitals in Barcelona were reviewed retrospectively. Two hundred consecutive patients with biopsy-proven GCA were studied. Thirty-two patients developed irreversible cranial ischemic complications. The duration of clinical symptoms before diagnosis was similar in patients with and those without ischemic events. Patients with ischemic complications less frequently had fever (18.8% versus 56.9%) and weight loss (21.9% versus 62%) and more frequently had amaurosis fugax (32.3% versus 6%) and transient diplopia (15.6% versus 3.6%). Patients with ischemic events had lower erythrocyte sedimentation rates (ESR) (82.7 mm/hour versus 104.4 mm/hour) and higher concentrations of hemoglobin (12.2 gm/dl versus 10.9 gm/dl) and albumin (37.4 gm/liter versus 32.7 gm/liter). Clinical inflammatory status and biologic inflammatory status were defined empirically (clinical: fever and weight loss; biologic: ESR > or =85 mm/hour and hemoglobin < 11.0 gm/dl). Patients not showing a clinical and biologic inflammatory response were at high risk of developing ischemic events (odds ratio [OR] 5, 95% confidence interval [95% CI] 2.05-12.2). The risk was greatly reduced among patients with either a clinical (OR 0.177, 95% CI 0.052-0.605) or a biologic (OR 0.226, 95% CI 0.076-0.675) inflammatory reaction. No patient with both a clinical and a biologic response developed ischemic events. The presence of a strong acute-phase response defines a subgroup of patients at very low risk of developing cranial ischemic complications. Our findings provide a rationale for testing less aggressive treatment schedules in these individuals. Conversely, a low inflammatory response and the presence of transient cranial ischemic events provide a high risk of developing irreversible ischemic complications and require a prompt therapeutic intervention.