www.centauro.it Interventional Neuroradiology 18: 33-41, 2012 Persistent Neurological Deficit from Iodinated Contrast Encephalopathy Following Intracranial Aneurysm Coiling A Case Report and Review of the Literature S. Leong, N.F. Fanning Department of Radiology, Cork University Hospital; Cork, Ireland Key words: contrast, neurotoxicity, interventional neuroradiology, coiling, deficit Summary Neurotoxicity from iodinated contrast agents is a known but rare complication of angiography and neurovascular intervention. Neurotoxicity results from contrast penetrating the bloodbrain barrier with resultant cerebral oedema and altered neuronal excitability. Clinical effects include encephalopathy, seizures, cortical blindness and focal neurological deficits. Contrast induced encephalopathy is extensively reported as a transient and reversible phenomenon. We describe a patient with a persistent motor deficit due to an encephalopathy from iodinated contrast media administered during cerebral aneurysm coiling. This observation and a review of the literature highlights that contrast-induced encephalopathy may not always have a benign outcome and can cause permanent deficits. This potential harmful effect should be recognised by the angiographer and the interventionalist. Introduction Iodinated contrast induced encephalopathy is a rare complication of angiography. It was first reported in 1970 as a transient cortical blindness after coronary angiography 1. Clinical manifestations include encephalopathy, seizures, cortical blindness and focal neurological deficits. Imaging is important in confirming the diagnosis and in excluding thromboembolic and haemorrhagic complications of angiography 2. Typical CT findings include abnor- mal cortical contrast enhancement and oedema, subarachnoid contrast enhancement, and striatal contrast enhancement. Since the first clinical description, there are 39 CT/MR confirmed cases of contrast-induced encephalopathy in the English language medical literature with documented clinical follow-up, summarized in Tables 1 and 2. Prognosis is generally reported as favourable with rapid recovery 2-25. There are two reports of persistent visual field deficits following contrast-induced encephalopathy 26,27. Here, we describe a patient with a persistent neurological deficit following a contrast-induced encephalopathy after endovascular aneurysm treatment. A literature review reveals eight cases of autopsy proven fatal cerebral oedema due to contrast neurotoxicity 2830. This report highlights the neurotoxic potential for iodinated contrast media to result in a permanent neurological deficit. Case Report A 50-year-old woman on screening CT angiogram was found to have three cerebral aneurysms: 7 mm paraophthalmic artery, 4 mm left middle cerebral artery, and 5 mm left carotid cave aneurysms. Risk factors for aneurysm formation included a family history of subarachnoid haemorrhage (sibling died following middle cerebral artery aneurysm rupture), hypertension and smoking. 120 mL of Iohexol (Omnipaque 300, GE Healthcare Ireland, Cork, Ireland), a low osmolar non-ionic contrast 33 Persistent Neurological Deficit from Iodinated Contrast Encephalopathy Following Intracranial Aneurysm Coiling agent, was used for the CT angiogram without complication. She underwent successful coiling of the paraophthalmic artery aneurysm using a balloon remodeling technique. The patient had received a total of 220 mL of Iopramide (Ultravist 300, Bayer Healthcare Pharmaceuticals, Wayne, NJ, USA), a low osmolar non-ionic contrast agent. The final angiogram showed occlusion of the distal dome of this aneurysm with some filling of the proximal lobe. All arteries were shown to be patent. Immediately following the procedure the patient had a complete right hemiparesis (face, arm and leg, power 0/5), sensory loss and right-sided neglect. A non-contrast CT brain within one hour of the coiling showed oedema in the left cerebral hemisphere, involving the frontal, parietal and occipital lobes (Figure 1). There was no haemorrhage or infarct. She was commenced on dexamethasone and mannitol. By day 2, her motor deficit was unchanged but her right-sided neglect had resolved. CT brain studies on day 3 and day 7 showed a progressive decrease in the cortical oedema in most of the left hemisphere, but with residual oedema in the peri-rolandic region. MRI on day 11 showed persistent oedema in the precentral and postcentral gyri (Figure 1). There was no restricted diffusion or infarct. There was a slow progressive clinical improvement, and on discharge at day 20, the right arm and leg motor weakness had improved to power 3/5, but there was right-sided spasticity with hyperreflexia and clonus. Her sensory symptoms had resolved. Three-month follow-up MRI showed resolution of the perirolandic oedema but with high signal in keeping with gliosis in the motor cortex (Figure 1). Follow-up cerebral angiography at one year showed occlusion of the paraophthalmic aneurysm. On this occasion 100 mL of Iohexol (Omnipaque 300) was used without issue. At one year, the patient had no motor power deficit but had persistent spasticity in her right hand and leg. This deficit caused some lifestyle restriction but she was able to care for herself (modified Rankin Score 2). Discussion Iodinated contrast media are reported to disrupt the blood-brain barrier temporarily causing an encephalopathy that is usually self-limiting. We describe a case that was not self-limiting. Contrast encephalopathy has been report34 S. Leong ed following angiography of most vascular territories 2,5,15,16,24,31,32, and also following endovascular aneurysm treatment 19,26,27,33. Transient cortical blindness is the most frequent reported clinical presentation. The reported incidence is 0.06% of patients undergoing coronary angiography 32, 0.3%-1% of patients undergoing vertebral angiography 31,34 and 2.9% (4/139) with endovascular coil treatment of posterior circulation aneurysms 27. Clinical effects of neurotoxicity from iodinated contrast agents include encephalopathy, seizures, cortical blindness and focal neurological deficits. Contrast encephalopathy is extensively reported to have a benign clinical course 2-25,35. Table 1 summarises the published cases in the English language literature of CT proven contrast encephalopathy with clinical followup. From these studies, neurological recovery occurs at a median time of 2.5 days [range, 0.230 days]. We have shown that contrast encephalopathy may result in a persistent neurological deficit. Table 2 summarises the available data on published cases of proven contrast encephalopathy with persistent deficits or death. These include reports of persistent visual field defects 26-27, retrograde amnesia 36,37 and fatal cerebral oedema following iodinated contrast administration 28-30,38. Junck and Marshall reported a clear case of contrast overdose 28, where 15.5 ml/kg of body weight of diatrizoate meglumine was given, similar to the median lethal dose (LD50) of 10-20 mg/kg in most species 39. All these fatal cerebral oedema cases involved the use of high osmolar contrast agents. While high osmolar contrast agents are no longer used in routine practice, contrast encephalopathy is reported with all types of contrast agents, and these cases highlight the potential for iodinated contrast agents to cause fatal cerebral oedema. Diagnosis of contrast encephalopathy is important as it may have a similar presentation to embolic, haemodynamic, and haemorrhagic complications following angiography or endovascular intervention. It is essential to have a post treatment angiogram that shows no arterial branch occlusions and a CT or MRI study that shows no acute infarct. Cases of contrast encephalopathy usually show characteristic CT brain findings – abnormal cortical contrast enhancement and oedema, subarachnoid contrast enhancement, striatal contrast enhancement – if the CT is performed soon after presentation 27. However, recent reports have also highlight- www.centauro.it Interventional Neuroradiology 18: 33-41, 2012 A B C D Figure 1 A) Non contrast CT brain immediately following coiling shows abnormal cortical contrast enhancement and edema in the left hemisphere and subarachnoid contrast enhancement. B) Axial FLAIR image on day 11 post coiling shows residual signal change particularly in the precentral and postcentral gyri. C) Contrast T1-weighted image on day 11 shows enhancement in the precentral gyrus, indicating persistent breakdown in the blood-brain barrier. D) Axial FLAIR image three months post coiling shows persistent signal change in the precentral gyrus, consistent with gliosis (arrow). ed that asymptomatic contrast enhancement and oedema of the cortex is a fairly common finding and reported in 23-54% of CTs performed within two hours of uneventful emboli- zation of cerebral aneurysms 40-42. The enhancement resolves by 25 hours in most cases. Diagnosis of contrast encephalopathy is therefore made by finding typical CT findings in a symp35 36 Carotid artery Aorta, Coronary & Carotid arteries Abdominal aorta Renal artery Aortocoronary bypass graft F/53 F/72 Numaguchi et al. (1984) 16 Carotid artery Vertebral artery Carotid artery Vertebral artery Arch, Carotid & Vertebral arteries Aortic arch Coronary artery Aortic arch Coronary artery Coronary artery M/71 M/55 Kinn & Breisblatt (1991) 12 Parry et al. (1993) 17 M/55 F/71 Sticherling et al. (1998) 21 Eckel et al. (1998) 5 to be continued in next page. M/62 Kamata et al. (1995) 11 M/62 M/70 Aortic arch Coronary artery Spinal angiogram Carotid artery Aorta M/64 F/68 Subclavian artery Aorta F/49 Shyn & Bell (1989) 20 Lantos (1989) 2 Henzlova et al. F/57 (1988) 10 F/74 Aortic arch F/59 Studdard et al. (1981) 22 Utz et al. (1988) 24 Arteriography Sex/ Age Reference None reported None reported None reported None reported None reported None reported Smoker, Hypertension Atherosclerosis Renal impairment; hypertension Hypertension Renal impairment Renal impairment; hypertension None reported Possible Risk Factors Coronary None reported artery stenting Spinal None reported angiography Coronary artery disease Coronary artery disease Coronary artery disease Carotid artery stenosis Carotid artery stenosis Carotid artery stenosis PCOM aneurysm Renal artery angioplasty Coronary artery disease Peripheral vascular disease Carotid artery stenosis Post carotid surgery check Meningioma investigation Indication for study No No Yes No Yes No No No No No Yes No No No Yes Non-ionic monomer low osmolar Ionic dimer low osmolar Non-ionic monomer low osmolar Non-ionic monomer low osmolar Ionic monomer high osmolar Non-ionic monomer low osmolar Non-ionic monomer low osmolar Ionic monomer high osmolar Ionic monomer high osmolar Ionic monomer high osmolar Ionic dimer low osmolar Ionic monomer high osmolar Ionic monomer high osmolar Ionic monomer high osmolar Ionic monomer high osmolar Previous Contrast agent angiography class Ioxaglate Iomeprol (Iomeron) Iopamidol 370 Iopamidol (Niopam) Diatrizoate meglumine; Iothalamate meglumine Diatrizoate meglumine Iohexol Iohexol (Omnipaque) Iothalamate meglumine Diatrizoate meglumine Ioxaglate (Hexabrix) Diatrizoate meglumine; Iothalamate meglumine Diatrizoate meglumine Diatrizoate meglumine Diatrizoate meglumine Contrast agent 360 280 170 270 228 50 22 24 38 12 30 200 250 120 80 60 150 CT brain region involved Bilateralparietooccipital Right-sided visual neglect; Wernicke’s aphasia Cortical blindness; confusion; amnesia Cortical blindness; clumsy right upper limb Severe headache; bilateral blindness; amnesia. Cortical blindness Cortical blindness (Anton); seizure; nystagmus; ophthalmoplegia Cortical blindness; confusion; fluent aphasia Cortical blindness; confusion; ophthalmoplegia Cortical blindness (Anton); confusion; amnesia Cortical blindness Cortical blindness; right facial paralysis; left hemiparesis Blindness and severe headache Bilateral occipital and left parietal lobes Bilateral cerebellum, occipital and thalami Bilateral occipital Bilateral occipital Bilateral occipital Bilateral occipital Bilateral occipital Bilateral occipital Left (temporoparieto) occipital Right occipital, tthalami, brainstem Bilateral occipital, basal ganglia Bilateral occipital Partial motor seizure Bilateral fronto-parietal 4d 5d 2d 3d 1d 2d 6d 10 d 3d 1d 2d 4-5 d 1d N/A 1d 1d 3d N/A 1d N/A N/A 1d N/A N/A N/A N/A 14 d Clinical CT resolution Brain resolution 5d 3d Cortical blindness (Anton); headache, myoclonus or seizure Partial motor seizure Right 1d Temporo-parietal Volume Presentation (mL) Table 1 CT/MRI confirmed blood brain barrier disruption following arteriography with favourable clinical outcomes: demographics, contrast agents, presentation, CT findings and outcome. Persistent Neurological Deficit from Iodinated Contrast Encephalopathy Following Intracranial Aneurysm Coiling S. Leong Carotid artery Vertebral artery Carotid artery F/52 ../52 F/74 Zwicker & Sila (2002) 25 Gellen et al. (2003) 8 Saigal et al. (2004) 19 Coronary artery Coronary artery Coronary artery Coronary artery Coronary artery Vertebral artery Carotid artery Coronary artery Carotid artery Coronary artery Coronary artery Coronary artery Tatli et al. (2007) F/52 ../61 ../78 F/70 F/54 M/80 M/51 M/56 Niimi et al. (2008) 27 Fang et al. (2009) 6 Guimaraens et al. (2009) 9 Alp et al. (2009) 3 M/47 Kocabay & Karabay (2011) 13 M/70 González et al. (2008) 63 Garcia de Lara et al. (2008) 7 23 Yazici et al. (2007) 62 F/70 Uchiyama et al. M/72 (2004) 33 Coronary artery F/74 Merchut & Richie (2002) 15 Lim & Radford F/63 (2002) 14 Coronary artery disease Coronary artery stenting Coronary artery stenting Right ICA aneurysm coiling Coronary artery disease Coronary artery disease Coronary artery stenting Coronary artery disease Coiling basilar apex aneurysm Coronary and carotid stenting Coronary artery disease Coiling basilar apex aneurysm Coiling anterior aneurysm Coronary artery disease Carotid artery stenting Coronary Coronary artery artery disease Abdominal aor- Renal ta artery Renal artery angioplasty Coronary Coronary artery artery stenting Carotid artery M/82 to be continued Dangas et al. (2001) 4 Diabetes None reported None reported Hypertension Hypertension None reported Renal impairment; hypertension Hypertension None reported None reported Hypertension; diabetes None reported Renal impairment; hypertension Hypertension Renal impairment; hypertension None reported Hypertension; diabetes Hypertension No No Yes No No No Yes No No No No No No No Yes No No Yes Non-ionic monomer low osmolar Non-ionic monomer low osmolar Non-ionic monomer low osmolar Non-ionic monomer low osmolar Non-ionic monomer low osmolar Non-ionic Non-ionic monomer low osmolar Non-ionic monomer low osmolar Non-ionic monomer low osmolar Conventional ionic contrast Non-ionic monomer low osmolar Non-ionic monomer low osmolar Non-ionic monomer low osmolar Non-ionic monomer low osmolar Non-ionic monomer low osmolar Non-ionic monomer low osmolar Non-ionic monomer low osmolar Ionic dimer low osmolar 220 300 250 62 1500 624 300 150 75 260 N/A 400 280 415 160 50 Iopromide 120 Iopromide 300 150 Iohexol 350 Iopromide Iohexol Not reported Not reported Iohexol 350 Iohexol 350 Iomeprol Iobitridol 350 (Xenetix) Iopamidol Iohexol 300 Iopamidol Ioversol (Optiray) Iopamidol Iopromide (Ultravist) Ioxaglate 4d 5d 2d Confusion; nausea Confusion; agitation; nausea; headache Gerstmann’s; left visual field deficit & hemiparesis; right gaze deviation Bilateral cortical blindness Right hemiparesis Vision loss to light perception Seizure Decreased consciousness and bilateral blindness Bilateral blindness Bilateral cortical blindness; headache; confusion; amnesia and disorientation Bilateral blindness; nausea and vomiting Right hemiparesis and motor aphasia. Occipital lobe Bilateral occipital and frontal lobes Right occipital lobe Right frontoparietal-occipital Left frontoparietaloccipital Occipital lobe (MRI) Right frontal 12 hours 8 hours 4d 2d 2d 30 d 1d Bilateral occipital, 10 d deep gray regions Bilateral occipital, 3 d deep gray regions Bilateral occipital 5 hours Left cerebral 7d cortex and left basal ganglia Bilateral occipital 3 d Visual loss; headache; Bilateral 1.5 d confusion; right frontal and pronator drift; and parieto-occipital aphasia Cerebellum, Bilateral complete 3d blindness bilateral occipital, thalami 1d Left Complete bilateral blindness; confusion parieto-occipital Confusion; left Right hemiparesis and fronto-parietal left neglect Headache; loss of Bilateral vision (light or objects); Occipital lobe impaired alertness Visuospatial disorder Bilateral Bilateral parieto-occipital 1.5 d 2d 4d 5d (MRI) 4d N/A 1d N/A N/A N/A 1.5 d N/A N/A N/A 4d 4d 1d 2d (MRI) www.centauro.it Interventional Neuroradiology 18: 33-41, 2012 37 38 F/68 F/73 F/62 M/41 Sharp et al. (1999) 36 Shinoda et al. (2004) 26 Niimi et al. (2008) 27 Aortic coarctation Tetralogy of Fallot with left Blalock-Taussig shunt Vertebral artery Vertebral artery Coronary artery Not stated Hypertension No Hypertension; Yes diabetes Hypertension No Hypoxaemia Superior cerebellar None reported Yes aneurysm coiling Contrast agent Non-ionic Non-ionic Non-ionic monomer Ionic monomer 180 Not specified Not specified 225 297 Diatrizoate 800 meglumine 350 Iohexol Non-ionic Iohexol monomer low osmolar Ionic Renografin 340 monomer 76 high osmolar CT brain region involved Clinical outcome Bilateral occipital and thalami Bilateral visual loss; agitation Cortical blindness; confusion Right parietal Bilateral occipital, basal ganglia, frontal Seizures; Bilateral dysphasia; frontal gait instability; and occipital bilateral postural tremor Confusion; amnesia; aphasia; and cortical blindness Generalised Cortex, basal seizures. Then ganglia and developed thalamus supraventricular tachycardia progressive hypertension Persistent visual field deficit documented at 4 years Persistent visual field deficit documented at 3 weeks Retrograde amnesia. Other symptoms resolved <7 d. Retrograde amnesia. Other symptoms resolved >6 d. Death at 33 hours Sudden apnoea No CT brain. Death at 15 and cardiac Autopsy hours arrest showed brain oedema, prominent gyri and tonsillar herniation Volume Presentation (mL) Ionic Urografin 76 monomer 76 high osmolar Previous Contrast angiography agent class Posterior inferior None reported No cerebellar aneurysm coiling Coronary artery stenting Aortocoronary Coronary artery bypass graft disease Aortic arch Junck & Marshall F/7 (1986) 28 Vranckx et al. (1999) 37 Cardiac chambers, aorta and pulmonary trunk Sex/Age Arteriography Indication for study Possible Risk Factors Shrivastava et al. M/10 (1985) 29 Reference Table 2 Contrast encephalopathy following arteriography with adverse clinical outcomes: demographics, contrast agents, presentation, CT findings and clinical outcome. Persistent Neurological Deficit from Iodinated Contrast Encephalopathy Following Intracranial Aneurysm Coiling S. Leong www.centauro.it tomatic patient after exclusion of thromboembolic and haemorrhagic complications. Reported demographic risk factors for clinically overt contrast encephalopathy include hypertension and renal failure. Of the imaging/ autopsy proven cases with clinical follow-up (Tables 1 and 2), 43% had hypertension and 15% renal failure; 45% of cases had no reported underlying risk factor. Some studies have suggested a correlation between contrast load and CT findings in asymptomatic patients 41,42; however, in symptomatic patients no such correlation was found 27. Also there was no specific contrast load that reliably led to contrast gyral enhancement 41 and indeed contrast encephalopathy has been reported in four patients with contrast (ionic and non-ionic media) volumes less than 40 mL 2. Most studies, including this case, suggest that prior and subsequent angiograms and procedures did not appear to result in the same complication 3,4,1012,22,25,27,35,37. Based on current knowledge, this complication appears to be an idiosyncratic reaction to contrast. This fact makes avoidance of contrast encephalopathy difficult. Why some patients experienced contrast gyral enhancement whereas others do not and why only a minority are symptomatic remains unknown and requires further investigation. The mechanism and causes of neurotoxicity is controversial. The blood-brain barrier is impermeable to radiographic contrast material under normal conditions. Transfer of contrast material increases if the blood-brain barrier is disrupted or if contrast material is overdosed or applied intra-arterially 16,43-46. In neurointerventional procedures, the contrast is injected repeatedly into a single vessel. As such, even if the total amount of contrast media is not excessive, the cumulative injections may contribute to blood-brain barrier breakdown 33. The neurotoxic effects of iodinated contrast media are usually attributed to a temporary blood brain barrier disruption 47. Uchiyama et al. 33 found elevated concentration of CSF iodine in their index case and not in 4 control cases, supporting evidence of a temporary breakdown of the blood-brain barrier. The cause of the blood brain barrier disruption is variably attributed to the hyperosmolality and chemotoxicity of contrast media 2,16,21,28,43-56. Studies suggest that contrast media penetrates the blood-brain barrier as a function of dosage, contact time, concentration of anions in the material, and lipophilic Interventional Neuroradiology 18: 33-41, 2012 characteristics 27. Hyperosmolality, especially with older high osmolar contrast agents, is hypothesized to cause shrinkage of endothelial cells and open tight junctions 54. However, hyperosmolality per se is not a requirement to induce blood-brain barrier disruption. Transient cortical blindness and global amnesia has been reported with iodixanol, a non-ionic dimer with osmolality equivalent to plasma 57. In addition, animal studies showed that blood-brain barrier damage caused by carotid angiography with non-ionic monomeric and dimeric contrast media was not attributable to their osmolalities, but due to some other physical and/or chemical effects of these media on the blood-brain barrier 58. One such factor may be the endothelin family of peptides. Endothelin release can be induced by radiocontrast media, have been shown to increase human brain endothelial cell permeability and is implicated in the pathophysiology of disorders associated with blood– brain barrier injury, including posterior reversible leukoencephalopathy syndrome 59-61. Because of the transient and rare nature of this complication, no definitive evidence base exists for specific treatments. Some authors have described the use of intravenous dexamethasone and/or mannitol 2,9,26,27, whilst others appear to have settled for close observation of the patient in the immediate post procedure period 6. Conclusion Neurotoxicity from iodinated contrast agents is a rare complication of angiography and neurovascular intervention. The infrequency with which it is encountered makes it a diagnostic challenge. Diagnosis of contrast encephalopathy is made by demonstrating typical CT findings in a symptomatic patient after exclusion of thromboembolic and haemorrhagic complications. Our report and literature review show that contrast-induced encephalopathy has the potential to cause permanent neurological dysfunction. This potential harmful effect should be recognised by doctors performing cardiovascular angiography and interventions. The challenge of future experimental studies will be to define the risk factors and neurotoxic mechanism of iodinated contrast agents, knowledge that may help us avoid this complication. 39 Persistent Neurological Deficit from Iodinated Contrast Encephalopathy Following Intracranial Aneurysm Coiling S. Leong References 1 Fischer-Williams M, Gottschalk PG, Browell JN. Transient cortical blindness. An unusual complication of coronary angiography. Neurology. 1970; 20: 353-355. 2 Lantos G. 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