
==== Front
Ann Indian Acad Neurol
Ann Indian Acad Neurol
AIAN
Ann Indian Acad Neurol
Annals of Indian Academy of Neurology
0972-2327
1998-3549
Wolters Kluwer - Medknow India

39196808
AIAN-27-403
10.4103/aian.aian_548_24
Brief Communication
Contrast-Induced Encephalopathy: A Case Series Analysis
Stebner Alexander 123
Bosshart Salome 12
Hainc Nicolin 4
Nierobisch Nathalie 4
Zedde Marialuisa 5
Pascarella Rosario 6
Goyal Mayank 12
Ospel Johanna 12
1 Department of Diagnostic Imaging, Foothills Medical Centre, University of Calgary, Canada
2 Department of Clinical Neurosciences, Foothills Medical Centre, University of Calgary, Canada
3 Institute of Radiology, Cantonal Hospital Münsterlingen, Münsterlingen, Switzerland
4 Department of Neuroradiology, Clinical Neuroscience Center, University Hospital Zurich, University of Zurich, Zurich, Switzerland
5 Neurology Unit, Stroke Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
6 Neuroradiology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
Address for correspondence: Dr. Johanna Ospel, Department of Diagnostic Imaging and Clinical Neurosciences, Foothills Medical Centre, University of Calgary, Calgary, Alberta, Canada. E-mail: johannaospel@gmail.com
Jul-Aug 2024
22 8 2024
27 4 403407
09 7 2024
08 8 2024
11 8 2024
Copyright: © 2024 Annals of Indian Academy of Neurology
2024
https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
Background:

Contrast-induced encephalopathy (CIE) is a rare adverse event linked to intravascular use of iodine-containing contrast media. The prevalence of CIE could increase in the future due to growing numbers of endovascular procedures. We provide insights from a case series of 7 patients.

Methods:

Cases from 3 centers were collected based on existing academic collaborations, and key factors were extracted to illustrate development and management of CIE.

Results:

In our retrospective case-series analysis of 7 cases from 3 countries, affected patients had an equal distribution of sex (4 women, 3 men) and a median age of 75 (IQR 63-77). Common risk factors included hypertension (5/7), hyperlipidemia (5/7), previous stroke (3/7), and type 2 diabetes (3/7). CIE developed in 3 cases after endovascular thrombectomy (EVT) for stroke, in 2 cases after aneurysm treatment, in 1 case after cardiac catheterization, and in 1 case after diagnostic computed tomography (CT) angiography without an endovascular procedure. The median procedure time was 48 min (IQR 40-81). All patients received non-ionic, low-osmolar contrast agents with volumes ranging from 100-300 ml. Symptom onset was close to contrast administration, with stroke-like neurological deficits being most common (4/7). Prednisolone was the most frequently used medication to treat the symptoms (4/7). Symptom resolution occurred in 4 out of 7 patients within two to several days, and 1 patient died, but without clear connection to CIE.

Conclusion:

CIE is a rare and possibly underrecognized condition, but fortunately, with a favorable outcome in most cases.

CIE
contrast-induced encephalopathy
contrast agents
endovascular therapy
iodine contrast
neurotoxicity
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pmcINTRODUCTION

Contrast-induced encephalopathy (CIE) is a rare, sporadic condition of neurotoxicity affecting patients after they receive higher dose of intravascular, mostly intraarterial, iodine contrast agents during interventional procedures like endovascular thrombectomies (EVTs) for acute ischemic strokes or cardiovascular interventions for acute coronary syndrome.[1] Patients with end-stage renal failure and hypertension with direct injection of contrast media into the aortic arch are more likely to suffer from this condition.[2] Men and women are both equally affected, with the elderly population predominantly affected with a median age of 63 years.[1] The cause remains unclear, but the most popular hypothesis is that a breakdown of the blood–brain barrier (BBB) facilitates contact of the contrast media with neurons, which causes altered excitability and neuronal dysfunction.[3] The most common symptoms are neurologic deficits with typical cortical blindness and reduced consciousness; in addition, confusion, aphasia, or hemiparesis can occur close to the endovascular procedure within 1–12 h.[45] Clinicians struggle to confidently diagnose this condition and often feel uncomfortable managing it.[6] Neuroimaging is obtained mostly to exclude differential diagnosis such as intracerebral hemorrhage, which may look similar to iodinated contrast extravasation. This renders magnetic resonance imaging (MRI) and dual-energy computed tomography (DECT) superior to noncontrast CT (NCCT) in diagnosing CIE.[7] Most frequent imaging findings are cortical contrast enhancement and cortical/sulcal effacement. Imaging findings usually show complete regression after 1–3 days.[1] Often, mass effect with edema is visible with contrast staining as a sign of BBB breakdown, but sometimes no radiographic features are visible.[8] So far, there are no existing treatment guidelines, and management is based on a case-by-case decision. In all case reports published so far, a rather conservative medical management approach was chosen with IV fluids, corticosteroids, and antiseizure therapy, as well as dialysis in dialysis-dependent patients.[4] Complete recovery within 24–72 h is observed in 85% of patients, but 3% of patients have been reported to die from this condition.[4] Patients may need mechanical ventilation and intensive care until symptom resolution occurs.[4] We present a case series of seven patients from three different countries who suffered from this condition, illustrate how the diagnosis was made, and provide the workflows that were initiated. We also provide more detailed clinical context and imaging data for two exemplary patients.

METHODS

Cases from three centers were collected based on existing academic collaborations. The University Hospital of Zurich provided two cases from their database. Four cases were contributed by the University of Modena and Reggio Emilia in Italy, and one case was provided by the Radiological Institute at the University of Calgary. Cases were de-identified by changing patient age, sex, and other patient characteristics without altering the accuracy of the clinical description. Key factors were extracted to compare different baseline characteristics such as sex, age, comorbidities, glomerular filtration rate (GFR), prior medications, and the indication that led to use of contrast agent. Procedural information included the type of the procedure, duration of the procedure, injected contrast volume, and the type of contrast agent used. In addition, information related to CIE was collected, such as the time of symptom onset, symptoms, diagnostic criteria, and treatment. Radiographic assessments in the acute phase were described, as well as clinical course and outcomes, including the National Institute of Health Stroke Scale (NIHSS) score, symptom resolution, and discharge medication. Continuous variables are displayed in medians with interquartile ranges (IQRs), and categorical variables are reported as counts and percentages.

RESULTS

In our analysis of retrospectively collected case series of seven cases from three countries, we found four (57%) female and three (43%) male patients who presented to the hospital between July 2016 and February 2024. The median age was 75 years (IQR 63–77). Common risk factors were hypertension (5/7 patients), hyperlipidemia (5/7 patients), previous stroke (3/7), and type 2 diabetes (3/7). Three out of seven patients developed CIE after EVT for stroke, two after aneurysm treatment, one after cardiac catheterization, and one after a diagnostic digital subtraction angiography to rule out a cerebral vascular malformation. One of the stroke patients did not receive an endovascular procedure and developed CIE after contrast admission for repeated diagnostic imaging, but the patient was receiving the highest amount of contrast (320 ml total) among all the cases presented [Table 1]. The median procedural duration was 48 min (IQR 40-81 min, 6/7), while one patient did not receive an endovascular procedure. All patients received nonionic, low-osmolar contrast agent (iopromide, iobitridol, iohexol, and iomeprol) with a volume ranging from 100 to 300 ml. Two patients had preexisting chronic kidney disease. The median GFR was 68 ml/min (IQR 47–77 ml/min), and the median procedural systolic blood pressure was 124 mmHg (IQR 118–151, 6/7). For two patients, the exact time of symptom onset was not clear due to underlying stroke and patients still being intubated after the EVT procedure. Three patients developed symptoms during or directly after the procedure and two after 3 and 7 h, respectively. Four patients experienced transient hemiparesis, two patients had seizures, aphasia, and headache, and one patient presented with cortical blindness. In six out of seven patients, the diagnosis of CIE was made immediately after symptom onset and/or neuroimaging and in one case, retrospective diagnosis was made after excluding other differential diagnoses. In two out of seven cases, the diagnosis was made only based on imaging findings. Prednisolone was the most frequently used medication for CIE (4/7 cases), while two patients did not receive any kind of specific therapy and one patient was treated with antihypertensives. One patient died, most likely due to a severe posterior circulation stroke with brain stem involvement. However, it is unclear whether CIE contributed to or caused the death. Two stroke patients did not fully recover during their hospital stay with inconclusive assessment of residual stroke symptoms to ischemic brain injury or CIE, and four patients improved after a median of 48 h (IQR 23–90 h). Patient characteristics are summarized in Table 1.

Table 1 Patients characteristics

Clinical information		
Sex (female)	4/7	
Age in years	75 (63-77)	
Risk factors	
    Hypertension	5/7	
    Hyperlipidemia	5/7	
    Previous stroke	3/7	
    Diabetes mellitus type 2	3/7	
    Chronic kidney disease	2/7	
    Smoking	2/7	
    Coronary artery disease	2/7	
    Asthma	1/7	
    GFR (ml/min)	68 (47-77)	
Diagnosis	
    Stroke	3/7	
    Brain aneurysm	2/7	
    NSTEMI	1/7	
    Brain hemorrhage	1/7	
Procedural information	
    Procedure type	
        EVT	2/7	
        Aneurysm coiling	2/7	
        Cardiac catheterization	1/7	
        Diagnostic angiography	1/7	
        CT	1/7	
    Procedure length in min	47.5 (40-81.3)/(6/7)	
    Procedural blood pressure (mmHg)	124 (118-151) (6/7)	
CIE-specific information	
    Symptom onset	<7 h (5/7)	
Symptoms CIE	
        Stroke like	4/5	
        Headache	2/5	
        Seizure	2/5	
        Blindness	1/5	
    Treatment	
        Prednisolone	4/7	
        Antiepileptic drugs	2/7	
        Nonspecific	2/7	
        Blood pressure control (<160 mmHg)	14% (1/7)	
Clinical development and outcome	
    Initial NIHSS	7 (1.5-15)/(6/7)	
    Follow-up NIHSS	4.5 (3.5-14)/(4/7)	
    Discharge NIHSS	3 (0.5-14)/(5/7)	
    Clinical resolution (days)	2 (0.9-4.5)/(4/7)	
All categorical variables are represented as numbers and continuous variables as median (IQR). CIE=contrast-induced encephalopathy, CT=computed tomography, EVT=endovascular thrombectomy, GFR=glomerular filtration rate, IQR=interquartile range, NIHSS=National Institutes of Health Stroke Scale, NSTEMI=non-ST-elevation myocardial infarction

Case 1: CIE after cardiac angiography

The patient was admitted for coronary catheter angiography due to a non-ST-elevation myocardial infarction on the basis of a preexisting coronary single-vessel disease. Catheter angiography showed a high-grade stenosis of the circumflex artery. During the intervention, after infusion of approximately 110 ml of contrast media, the patient developed aphasia and a right sensorimotor hemisyndrome; hence, the intervention was stopped and the patient was transferred to the stroke unit. The initial NIHSS score was 8. NCCT and subsequent CT angiography (CTA) of the brain did not reveal any infarcts or higher-grade vascular stenoses, but subtle sulcal hyperdensities and mild cortical swelling were seen in the left frontal lobe [Figure 1a]. MRI done on the next day showed a small infarction on the right hemisphere, which did not explain the clinical deficits [Figure 1b]. Pre-contrast T1-weighted imaging reveals no evidence of hemorrhage [Figure 1c]. In addition, leptomeningeal and parenchymal contrast enhancement was recognized, which was interpreted as a BBB breakdown suggestive of CIE after cardiac catheterization [Figure 1d]. Secondary prophylaxis with aspirin and a statin was established and the patient’s condition improved quickly. Aphasia and hemiparesis regressed to an NIHSS score of 4 two days after the cardiac intervention and to NIHSS 0 after a total of 3 days. No additional follow-up imaging was performed.

Figure 1 Illustration of Case 1: (a) NCCT shows no signs of early ischemic changes, with only mild hyperdensities in the sulci of the left frontal lobe representing contrast (white arrow) given in previous cardiac intervention. (b) DWI shows only one small spot of diffusion restriction on the right posterior parietal lobe (black arrow) that did not explain the patient’s symptoms. (c) Pre-contrast T1w imaging shows no signs of hemorrhage. (d) Post-contrast FLAIR imaging shows BBB breakdown. BBB = blood–brain barrier, NCCT = noncontrast computed tomography, T1w = T1-weighted, DWI = Diffusion weighted imaging, FLAIR = Fluid attenuated inversion recovery

Case 2: CIE after aneurysm coiling

The patient presented to the emergency department after having felt unwell the day before with difficulties understanding her colleagues and now with severe headache and mild right hemiparesis. An emergency CTA revealed a left M2 branch occlusion of the middle cerebral artery, which was successfully treated with IV alteplase. In addition, CTA revealed an incidental finding of middle cerebral artery (MCA) aneurysm on the right side [Figure 2a]. This finding was discussed with the patient and an endovascular aneurysm treatment was planned. The aneurysm treatment was successful, but 3 h later, the patient complained about a sudden onset of headache with mild hemiparesis and a sequence of focal seizures followed by a generalized seizure. NCCT acquired at the onset of symptoms showed widespread sulcal effacement and right hemisphere cortical swelling with mild mass effect and compression of the ventricular system [Figure 2b]. Fluid-Attenuated Inversion Recovery (FLAIR) sequence showing entirely negative MRI findings for stroke or hemorrhage [Figure 2c]. Treatment with IV diazepam and prednisone was initiated, and the patient was transferred to the intensive care unit. The follow-up CT on the next day showed a progressive reduction of the swelling, with symptom resolution achieved on the sixth day [Figure 2d]. Unfortunately, the patient had to be intubated and she developed a critical illness neuropathy while she was in the intensive care unit and was discharged to in-patient rehabilitation several days later for weaning from tracheostomy and treatment of polyneuropathy.

Figure 2 Illustration of Case 2: (a) Angiography for treatment of the middle cerebral artery aneurysm (white arow). (b) NCCT shows significant contrast staining and swelling in the middle cerebral artery territory on the right side. (c) FLAIR sequence with completely negative MRI findings for stroke or hemorrhage. (d) Follow-up imaging shows significant decrease in swelling and contrast staining. MRI = magnetic resonance imaging, NCCT = noncontrast computed tomography

DISCUSSION

In this short case series analysis, we investigated seven cases of CIE from three different countries, which showed different clinical scenarios and management approaches to CIE. The patients' baseline characteristics, including sex and comorbidities such as hypertension, hyperlipidemia, and chronic kidney disease, mostly agree with previously published studies, with hypertension being the most frequent comorbidity.[145] The median age in our group was 75 years, that is, slightly higher than previously reported in the literature.[1459] Previous studies have described that greater intraprocedural blood pressure variability could trigger CIE development after the intervention.[510] However, in our case series, intraprocedural blood pressure was not documented, and only single-point measurements were available. Two of our patients had preexisting chronic kidney disease, which is also described to be a relevant comorbidity.[4] In three out of seven cases, patients developed CIE after a stroke, with two of these cases undergoing mechanical thrombectomy. One patient developed CIE after undergoing only the diagnostic imaging for his acute ischemic stroke and received solely IV thrombolysis without EVT. Although rare, cases of CIE occurring after diagnostic cross-sectional imaging exist,[11] and this patient received through shortly repeated imaging the highest amount of contrast (320 ml) among all the seven cases. However, the amount of contrast is likely just one of several factors, as there are also case reports of patients developing CIE after receiving low amounts of low-osmolar, nonionic contrast agents.[12] In fact, all our patients received the generally considered safe low-osmolar, nonionic contrast agents.[13] There are few documented cases for CIE occurring after EVT in stroke patients in the literature.[9] In this case series, we had two patients in whom the diagnosis of CIE was made based on imaging findings only, since the patients were still intubated after their stroke could not be assessed and because the clinical symptoms of CIE could not be differentiated from residual stroke symptoms. Notably, contrast extravasation or contrast staining is a relatively common finding on CT scans following neurointerventional procedures, which is observed in up to 27% of patients.[14] In addition, benign contrast staining is commonly observed beyond the infarct core in 13% of stroke patients after EVT, and differentiation between residual stroke symptoms and those related to possible impact of contrast neurotoxicity is hard.[15] The breakdown of BBB appears to be the pathophysiological mechanism responsible for contrast leakage and development of symptoms for CIE.[3] A clear visible breakdown of BBB was observed in one patient even after 1 day, along with gadolinium contrast enhancement in MRI. Four out of seven patients showed stroke-like symptoms, consistent with findings from previous studies.[459] Since no established guidelines exist for CIE, the treatment varies widely. In our small case series, prednisolone therapy followed by antiseizure medication was most commonly used, consistent with other studies. This reflects the fact that CIE treatment is determined on a case-by-case basis and is usually a symptomatic therapy depending on the clinical presentation. It also highlights the lack of evidence-based treatment recommendations, and thus a high degree of uncertainty and difficulty clinicians often face in diagnosing this condition.[6]

Limitations

This case series analysis has several limitations. (i) The cases were analyzed retrospectively without prior predefined characteristics. Consequently, some data were not documented during the patients' clinical presentation and could not be acquired, leading to potential gaps. For example, the total amount of contrast used is only an approximate amount in many cases, and the exact amount of contrast for each side was also not documented. (ii) Patients did not have long-term follow-ups and were sometimes discharged with residual symptoms. We cannot exclude the possibility of permanent damage after CIE, nor can we determine when complete symptom resolution occurred. Lastly, (iii) the diagnosis of CIE was based on clinicians' perspective and was sometimes made solely based on imaging characteristics without worsening of patient symptoms. Therefore, asymptomatic contrast staining cannot be excluded in postprocedural patients in whom clinical examination was impossible due to the wake-up phase after anesthesia.

CONCLUSION

CIE is a rare, possibly underrecognized condition, but fortunately, it has a favorable outcome. Further research is necessary to enhance our understanding of its pathophysiology and management.

Financial support and sponsorship

Alexander Stebner received a stipend for his Research Fellowship in Calgary from the Swiss Society of Radiology. Mayank Goyal holds grants from Johnson and Johnson and Medtronic and is a consultant to Medtronic, Mentice, Microvention, Philips, and Stryker. Johanna Ospel is a consultant for Nicolab.

Conflicts of interest

There are no conflicts of interest.
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