Contrast-induced encephalopathy (CIE) is a rare complication of iodinated contrast administration during endovascular treatments, with a described incidence of less than 2% (1,2). CIE most commonly presents as an encephalopathy, ranging from mild confusion to decreased consciousness, with or without focal neurological deficits, including cortical blindness, motor or sensory deficit, aphasia, as well as headache and/or epileptic seizures (3-6). Symptoms may start during neurovascular treatment, immediately after or a few hours afterwards and usually progress over several hours (4, 5). The first case description goes back to 1970, with a report of a woman who experienced transient cortical blindness after a coronary angiogram (7). Over the last few years, CIE is becoming a more and more relevant neurological clinical entity and, with the expanded use of contrast-based diagnostic imaging and endovascular treatments in acute ischaemic stroke, its incidence is expected to increase.

The exact pathophysiology of CIE is not well understood, but temporary disruption of the blood-brain barrier is thought to give way to possible neurotoxic effects of contrast agents. Identified CIE risk factors include patient characteristics, as hypertension, diabetes mellitus, chronic kidney disease and prior stroke (1,3,8), as well as contrast- and treatment-related factors, like higher contrast volume, hyperosmolar-/ionic contrast agents and intra-arterial administration of iodinated contrast (1).

Diagnosis is often challenging because of the heterogeneous symptoms and radiographic features, which are non-specific. Indeed, CIE symptoms closely mimic other causes of neurological deterioration after neurovascular treatment, such as intracerebral haemorrhage (ICH), recurrent ischaemic stroke, posterior reversible encephalopathy syndrome (PRES), post stroke seizures or post-ictal phase, residual sedation, metabolic disturbances such as hypoglycaemia or delirium. Therefore, CIE entity is a diagnosis by exclusion. Neuro-imaging is a pivotal step for helping differential diagnosis, especially for identifying ICH, recurrent ischaemic stroke and PRES. Brain CT features of CIE include parenchymal oedema with loss of grey-white matter differentiation and/or effacement of cortical sulci and contrast enhancement of cortex or subarachnoid space, mostly in the hemisphere of contrast administration, but not limited to a vascular territory. Accordingly, brain MRI may show T2 hyper-intense cortical lesions and new lesions with diffusion restriction not limited to the affected vascular territory (1-4). However, both CT and MRI may also appear normal, especially in the early phase (1,4).

At this moment, there is no standard treatment of CIE. Usually, vigorous hydration is recommended. The efficacy of steroids and mannitol in reducing cerebral oedema remains controversial, and these drugs are not routinely recommended (1,4). When seizures occur, anticonvulsive drugs should be introduced. Importantly, when CIE is a likely diagnosis, the use of additional contrast-based imaging should be very carefully considered. Indeed, CIE has been previously regarded as a transient and benign complication of contrast-administration, characterised by a complete resolution within one to three days, questioning the benefit of specific treatments. However, recent publications on CIE occurrence after neurovascular procedures, reported an association between CIE and poor functional outcome at three months, without impact on mortality-risk (3). In particular, a meta-analysis published in 2021 showed that 15% of patients required mechanical ventilation because of decreased consciousness, and one in ten patients did not completely recover (4).

In conclusion, CIE is a relevant neurological entity that clinicians should not underestimate. Because of the heterogeneous spectrum of clinical signs, it remains a challenging diagnosis. However, when a patient neurologically deteriorates after intravenous or intra-arterial iodinated contrast agents use, we suggest including CIE systematically in the differential diagnosis. Of note, its occurrence might not be as benign as often described and more research is needed to clarify its impact on clinical outcome.

References

1. Meijer FJA, Steens SCA, Tuladhar AM, van Dijk ED, Boogaarts HD. Contrast-induced encephalopathy-neuroimaging findings and clinical relevance. Neuroradiology. Jun 2022;64(6):1265-1268. doi:10.1007/s00234-022-02930-z
2. Zevallos CB, Dandapat S, Ansari S, et al. Clinical and Imaging Features of Contrast-Induced Neurotoxicity After Neurointerventional Surgery. World Neurosurg. Oct 2020;142:e316-e324. doi:10.1016/j.wneu.2020.06.218
3. Chu YT, Lee KP, Chen CH, et al. Contrast-Induced Encephalopathy After Endovascular Thrombectomy for Acute Ischemic Stroke. Stroke. Dec 2020;51(12):3756-3759. doi:10.1161/STROKEAHA.120.031518
4. Quintas-Neves M, Araujo JM, Xavier SA, Amorim JM, Cruz ESV, Pinho J. Contrast-induced neurotoxicity related to neurological endovascular procedures: a systematic review. Acta Neurol Belg. Dec 2020;120(6):1419-1424. doi:10.1007/s13760-020-01508-x
5. Harada Y, Kairamkonda SR, Ilyas U, et al. Pearls & Oy-sters: Contrast-induced encephalopathy following coronary angiography: A rare stroke mimic. Neurology. Jun 9 2020;94(23):e2491-e2494. doi:10.1212/WNL.0000000000009590
6. Spina R, Simon N, Markus R, Muller DW, Kathir K. Contrast-induced encephalopathy following cardiac catheterization. Catheter Cardiovasc Interv. Aug 1 2017;90(2):257-268. doi:10.1002/ccd.26871
7. Fischer-Williams M, Gottschalk PG, Browell JN. Transient cortical blindness. An unusual complication of coronary angiography. Neurology. (1970) 20:353–5. doi: 10.1212/WNL.20.4.353
8. Vigano M, Mantero V, Basilico P, et al. Contrast-induced encephalopathy mimicking total anterior circulation stroke: a case report and review of the literature. Neurol Sci. Mar 2021;42(3):1145-1150. doi:10.1007/s10072-020-04844-1

ESOC is Europe’s leading forum for advances in research and clinical care of patients with cerebrovascular diseases. ESOC 2023 will live up to its expectation, and present to you a packed, high quality scientific programme including major clinical trials, state-of-the-art seminars, educational workshops, scientific communications of the latest research, and debates about current controversies.

Registrations will open in November 2023 for ESOC 2023. Learn more here.

The concept of a polypill, i.e. a single pill combining effective single drugs for prevention of cardiovascular events, is as simple as compelling and has been discussed among researchers in cardiovascular medicine for almost two decades^1,2. Usually, the so-called polypill contains aspirin, one or more first line antihypertensive drugs, and a statin, by this combining the effects of lowering of cholesterol, blood-pressure lowering, and of an antiplatelet drug. All these effects are known to reduce adverse cardiovascular events, and the combination of multiple of these drugs in a single pill is proposed to improve patients’ adherence to medication, and to reduce the complexity and costs of prescription. Results of the EU-funded SECURE study³, which was just published and presented at the ESC congress 2022, add novel findings on the effect of a polypill for secondary prevention after myocardial infarction, which also may be of interest for stroke researchers.

In SECURE, patients were randomized within six months of myocardial infarction to secondary prevention using a polypill (including aspirin 100mg, ramipril 2.5, 5, or 10 mg and atorvastatin 20 or 40 mg) or usual care. The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, urgent revascularization, or ischemic stroke. A total of 2499 patients were randomized and followed for a median of 36 months. Assignment to the polypill group was associated with a significant reduction in occurrence of the primary endpoint, with a hazard ratio of 0.76 (95% confidence interval 0.60-0.96, p=0.02). Primary outcome events occurred in 118 of 1237 (9.5%) patients in the polypill group and in 156 of 1229 (12.7%) patients assigned to usual care. The most striking effect was observed for cardiovascular death, which occurred in 48 (3.9%) patients in the polypill group and 71 (5.8%) in the usual care group, representing an absolute reduction of 1.9% over a period of three years. Key secondary endpoints were also observed less frequently in the polypill group, while adverse events and all-cause mortality were comparable between groups. As expected, adherence to medication was higher among patients in the polypill group.

Previous polypill trials have mostly focused on the use of a polypill for primary prevention of cardiovascular events, such as the International Polycap Study 3 (TIPS-3)⁴, or broad inclusion of patients in a pragmatic approach, such as the PolyIran study⁵. In these studies, the use of a polypill was compared to placebo (TIPS-3), or non-pharmacologic interventions (PolyIran study). In contrast, SECURE tested the polypill approach in a setting of secondary prevention after myocardial infarction, and patients in the usual care group also received antiplatelets and medication for lowering of blood pressure and cholesterol, at the discretion of the treating physicians. The additional benefit of the polypill may be explained by the simplified approach resulting in improved adherence to these effective drugs. SECURE also differs to previous polypill studies by offering different polypills containing different doses of the individual drugs, thus allowing for a personalized adaption of the treatment strategy in case of insufficient risk factor control.

To summarize, the findings from SECURE suggest that a polypill adds to the current strategies of secondary prevention after myocardial infarction. Given these results and given the known problems with adherence to intake of drugs for secondary prevention after stroke, a polypill might also be a powerful tool for the prevention of recurrent strokes and other cardiovascular events in secondary prevention after stroke.

References

1. Wang TJ. The Polypill at 20 – What Have We Learned? N Engl J Med 2022.
2. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003; 326(7404): 1419.
3. Castellano JM, Pocock SJ, Bhatt DL, et al. Polypill Strategy in Secondary Cardiovascular Prevention. N Engl J Med 2022.
4. Yusuf S, Joseph P, Dans A, et al. Polypill with or without Aspirin in Persons without Cardiovascular Disease. N Engl J Med 2021; 384(3): 216-28.
5. Roshandel G, Khoshnia M, Poustchi H, et al. Effectiveness of polypill for primary and secondary prevention of cardiovascular diseases (PolyIran): a pragmatic, cluster-randomised trial. Lancet 2019; 394(10199): 672-83.

ESOC is Europe’s leading forum for advances in research and clinical care of patients with cerebrovascular diseases. ESOC 2023 will live up to its expectation, and present to you a packed, high quality scientific programme including major clinical trials, state-of-the-art seminars, educational workshops, scientific communications of the latest research, and debates about current controversies.

Registrations will open in November 2023 for ESOC 2023. Learn more here.

Anticoagulation with direct oral anticoagulants (DOACs) started early after acute ischemic stroke (IS) or transient ischemic attack (TIA) related to nonvalvular atrial fibrillation (NVAF) is critical to reduce the risk of recurrent stroke and systemic embolism.¹ The optimal timing to start anticoagulation, however, remains elusive.

A 1-3-6-12 rule has been largely adopted in clinical practice, with early DOAC initiation in TIA and later initiation (12 days or more) in severe stroke.¹ Such a timing, proposed on the basis of observational data and consensus/opinions, lacks support from (ongoing) randomized trials. In the meantime, stroke specialists are further shortening the timing for DOAC initiation, with the aim of reducing as much as possible the risk of stroke recurrence and systemic embolism.² This strategy has to take into account the risk of haemorrhagic transformation, which may have several contributors, such as the ischemic volume.²

In a recent paper in Stroke, Kimura and colleagues pooled data from several observational studies to define safety and efficacy of shortening the interval between index stroke and DOAC initiation.³ In a derivation cohort including mainly Japanese patients, they compared an early (n=785) and late (n=1012) DOAC initiation strategy for ischemic and bleeding outcomes across four stroke groups: TIA, mild stroke with, moderate stroke, and severe stroke. The early initiation strategy consisted in a 1-2-3-4 day DOAC initiation rule according to increasing severity of stroke. In the derivation cohort, the rate of recurrent ischemic stroke dropped from 3.9% with late initiation to 1.9% with early initiation (adjusted hazard ratio 0.50 [95% CI, 0.27–0.89]). Major bleeding occurred in six (0.8%) in the early group and 10 (1.0%) in the late group (aHR 0.81 [0.28–2.19]). In the external validation cohort (n=2063), ischemic stroke occurred in 13 patients (2.4%) of the early group and 33 (2.2%) of the late group (aHR 1.07 [95% CI, 0.54–2.00]. ICH occurred in one (0.2%) in the early and nine (0.6%) in the late initiation group (aHR 0.31 [0.02–1.65]).³

Overall, the results of this large collaborative studies suggest that a shorter delay of anticoagulation initiation (1-2-3-4 rule vs 1-3-6-12 rule according to stroke severity) could be feasible and may not carry an increase in risk of bleeding, with a potential higher efficacy among Japanese people.³

At the moment, the timing of anticoagulation resumption is investigated in four ongoing randomized trials (TIMING, OPTIMAS, ELAN, and START, Clinical trials identifier NCT02961348, NCT03759938, NCT03148457, NCT03021928, respectively), which differ in timing of randomization to DOAC initiation. Indeed, in TIMING and OPTIMAS anticoagulation is initiated no earlier than four days, while a severity-based timing is proposed in ELAN and START. Results from these trials are critically needed, as shorter initiation timing might benefit stroke patients.

References

1. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Europace 2016; 18: 1609–1678.

2. Paciaroni M, Caso V, Agnelli G, et al. Recurrent Ischemic Stroke and Bleeding in Patients With Atrial Fibrillation Who Suffered an Acute Stroke While on Treatment With Nonvitamin K Antagonist Oral Anticoagulants: The RENO-EXTEND Study. Stroke. Epub ahead of print 11 May 2022. DOI: 10.1161/STROKEAHA.121.038239.

3. Kimura S, Toyoda K, Yoshimura S, et al. Practical ‘1-2-3-4-Day’ Rule for Starting Direct Oral Anticoagulants after Ischemic Stroke with Atrial Fibrillation: Combined Hospital-Based Cohort Study. Stroke 2022; 53: 1540–1549.