Background: Contrast-induced neurotoxicity (CIN) is an increasingly observed event following the administration of iodinated contrast. It presents as a spectrum of neurological symptoms that closely mimic ischaemic stroke, however, CIN remains a poorly understood clinical phenomenon. An appreciation of the underlying pathophysiological mechanisms is essential to improve clinical understanding and enhance decision-making. Methods: A broad literature search of Medline (1946 to December 2022) and Embase (1947 to December 2022) was conducted. Articles discussing the pathophysiology of CIN were reviewed. Summary: The pathogenesis of CIN appears to be multifactorial. A key step is likely blood-brain barrier (BBB) breakdown due to factors including ischaemic stroke, uncontrolled hypertension, and possibly contrast agents themselves, among others. This is followed by passage of contrast agents across the BBB, leading to chemotoxic sequelae on neural tissue. Key Messages: This review provides a clinically oriented review on the pathophysiology of CIN to enhance knowledge and improve decision-making among clinicians.

With the increasing utilization of iodinated contrast agents in both diagnostic imaging and endovascular procedural settings, reports of contrast-induced neurotoxicity (CIN) have become more prevalent in the literature. CIN (also referred to as contrast-induced encephalopathy or acute transient contrast-induced neurologic deficit) was first described by Fischer-Williams et al. [1] in 1970, where a patient experienced transient cortical blindness following coronary angiography. In addition to visual deficits, other reported symptoms of CIN include sensory and motor deficit, aphasia, and impaired consciousness [2‒7]. Despite an increase in reports, the clinical understanding of CIN is limited. This becomes an especially significant concern in neurovascular procedures, in which ischaemic stroke is a known complication and closely resembles the symptomatology of CIN. The incidence of CIN has been estimated to be approximately 0.5% [8]; however, particularly following neurointervention, the rate of CIN has been reported to be as high as 3.5% [9, 10]. The symptoms of CIN are typically transient, although there have been reports of long-term neurological deficits and even death [7, 11, 12].

A better understanding of the pathophysiology of CIN is essential to providing optimal care. A recent survey demonstrated that 75% of clinicians believed that the pathophysiology of CIN was poorly understood in the clinical setting [13]. CIN remains a poorly understood clinical entity, and there remains a lack of formalized diagnostic criteria. We provide a comprehensive review on the state of knowledge on the pathophysiology of CIN to enhance knowledge and improve decision-making among clinicians.

A broad literature search was conducted of MEDLINE (1946 to December 2022) and Embase (1947 to December 2022). Key search terms comprised “contrast,” “neurotoxicity,” “encephalopathy,” “blindness,” and “deficit,” with Boolean operators used as appropriate. A broad search strategy was employed to include even articles that did not necessarily focus on pathophysiology so that reference lists could be assessed for relevance. Articles discussing the pathophysiology of CIN were included for review.

Utilization of iodine-based contrast dates back to the 1920s, when it was used for the purposes of urography [14, 15]. Iodinated contrast agents provide enhanced absorption and scatter of radiation energy used in imaging, allowing for greater visualization of structures, including the vascular anatomy. This is partly due to iodine’s molecular density and partly due to its chemical nature relating to outer shell electrons [16, 17]. Contrast enhancement is proportional to the amount of iodine as well as the concentration of radiation energy from imaging [18].

Classification

Iodinated contrast agents are conventionally formed by benzene rings bound to three iodine atoms. They can be classified according to their chemical structure as either monomeric (containing one benzene ring) or dimeric (containing two benzene rings) [19]. Additionally, contrast can be categorized as ionic and nonionic based on whether they dissociate into ions. In solution, ionic agents dissociate into separate ions and are highly osmolar, while nonionic compounds do not dissociate, having less effect on osmolality.

Contrast media can also be classified according to osmolality relative to serum. The normal serum osmolality is between 275 and 295 mOsm/kg. High-osmolality contrast media have 5–8 times the osmolality of plasma (1,200–2,400 mOsm/kg), while low-osmolality contrast media are iso-osmolar (290 mOsm/kg) to three times the osmolality of plasma (860 mOsm/kg) [20‒24]. High-osmolality contrast media were the first generation of iodinated contrast, although they have become increasingly replaced by low-osmolality contrast media in recent years due to lower rates of complications (such as nephrotoxicity [25]) as well as improved image enhancement [26]. For reference, the classification of commonly utilized contrast agents is summarized in Table 1 [27].

Table 1.

Iodinated contrast agents

Generic nameTrade nameIodine concentration, mg/mLChemical structureIonicityOsmolality
Iopromide  Ultravist® 150 (Bayer HealthCare)  150 Monomer Nonionic 328 
Iopamidol (408)  Isovue®-200 (Bracco)  200 Monomer Nonionic 413 
Ioversol (509) Optiray™ 240 (Guerbet) 240 Monomer Nonionic 502 
Iopamidol (510)  Isovue® 250 (Bracco)  250 Monomer Nonionic 524 
Iodixanol (550) Visipaque™ 270 (GE Healthcare) 270 Dimer Nonionic 290 
Iothalamate (600) Conray™ (Covidien) 282 Monomer Ionic 1,400 
Iopromide  Ultravist® 300 (Bayer Healthcare)  300 Monomer Nonionic 607 
Iodixanol (652) Visipaque™ 320 (GE Healthcare) 320 Dimer Nonionic 290 
Iopamidol (755)  Isovue® 370 (Bracco)  370 Monomer Nonionic 796 
Diatrizoate (760) MD-76™ R (Guerbet) 370 Monomer Ionic 1,551 
Generic nameTrade nameIodine concentration, mg/mLChemical structureIonicityOsmolality
Iopromide  Ultravist® 150 (Bayer HealthCare)  150 Monomer Nonionic 328 
Iopamidol (408)  Isovue®-200 (Bracco)  200 Monomer Nonionic 413 
Ioversol (509) Optiray™ 240 (Guerbet) 240 Monomer Nonionic 502 
Iopamidol (510)  Isovue® 250 (Bracco)  250 Monomer Nonionic 524 
Iodixanol (550) Visipaque™ 270 (GE Healthcare) 270 Dimer Nonionic 290 
Iothalamate (600) Conray™ (Covidien) 282 Monomer Ionic 1,400 
Iopromide  Ultravist® 300 (Bayer Healthcare)  300 Monomer Nonionic 607 
Iodixanol (652) Visipaque™ 320 (GE Healthcare) 320 Dimer Nonionic 290 
Iopamidol (755)  Isovue® 370 (Bracco)  370 Monomer Nonionic 796 
Diatrizoate (760) MD-76™ R (Guerbet) 370 Monomer Ionic 1,551 

The central nervous system (CNS) requires a closely regulated biochemical environment to function normally. The blood-brain barrier (BBB) acts as a selectively permeable membrane, allowing the passage of some molecules, while preventing the passage of others (Fig. 1) [28]. The anatomical structure of the BBB is unique from the rest of the body and is the mechanism by which it is able to control the influx and efflux of biological substances to and from the brain [29].

Fig. 1.

Simplified depiction of the BBB and possible mechanisms of contrast neurotoxicity.

Fig. 1.

Simplified depiction of the BBB and possible mechanisms of contrast neurotoxicity.

Close modal

The structure of the BBB is composed of three main cell types: (i) endothelial cells, (ii) pericytes, and (iii) astrocytes. The endothelial cells of brain capillaries are anchored to one another through transmembrane proteins, including occludin and claudin [28]. Unlike other regions of the body, the endothelial cells of the brain are tightly adherent to one another and form “tight junctions,” which greatly restrict the passage of biological substances when compared to other regions of the body [30]. In this way, endothelial cells form the principal physical barrier of the BBB [31].

Pericytes are located on the abluminal (outer surface of the lumen) of endothelial cells. These cells are important to BBB function and play an important role in regulating capillary blood flow, angiogenesis, and immune cell passage [32]. Additionally, pericytes have been suggested to be involved in the formation of the BBB during development [33].

Astrocytes are the most common cell in the brain and have a range of functions. Astrocyte foot processes surround capillaries in the CNS, providing metabolic and structural support to the BBB unit. In recent times, astrocytes have been suggested to play a more active role in the BBB, including regulating microcapillary blood flow [34]. Astrocyte foot processes represent the intersection between the “blood” and the “brain” of the BBB [29].

Altogether, the BBB has several functions that are vital to CNS function. The BBB is instrumental in regulating ionic and pH concentrations [35‒37], preventing passage of harmful proteins, and allowing passage of nutrients essential to neural function [35]. Alongside this, the BBB is responsible for protecting the CNS from neurotoxic biochemical substances, including contrast agents. Damage to the BBB will not only allow for the passage of neurotoxic contrast material but may also affect the closely controlled microenvironment in the CNS.

Under normal circumstances, iodinated contrast agents do not cross the BBB or do so in negligible amounts [38]. Damage to the BBB may allow contrast agents to cross the BBB and exert neurotoxic effects. Several factors have been suggested to lead to dysfunction of the BBB. Structural pathologies, for example, such as primary and metastatic brain tumours, have been reported to compromise the integrity of the BBB [39], which may allow contrast to enter the CNS.

Ischaemic stroke is also known to have a disruptive impact the integrity of the BBB [40] and consequently may be a predisposing factor in the development of CIN. Injury to the BBB occurs immediately after arterial occlusion, likely as a result of hypoxic damage to tight junctions and vascular endothelium, as well as cytotoxic oedema, which increase permeability [40, 41]. In the acute stage, neuroinflammation may further exacerbate BBB damage. In the weeks following the initial insult, multiple repair mechanisms take effect, including protective inflammation [42] and neoangiogenesis [43, 44]. In the chronic phase (>6 weeks), BBB integrity is significantly improved with upregulation of tight junction proteins [45] and neurogenesis [46]. Despite these repair mechanisms, it is likely that patients with ischaemic stroke will suffer from some degree of long-term BBB disruption, albeit to a lesser extent than in the acute stages following initial injury [40].

Similarly, it has been suggested that small vessel disease may have some relationship with BBB dysfunction [47, 48]. In the current literature, it is uncertain whether small vessel disease causes BBB damage or whether BBB disruption leads to small vessel disease. Nonetheless, the association between both entities appears to be relatively clear [49, 50]. In the setting of both ischaemic stroke and small vessel disease, BBB damage is linked to increased risks of cerebral haemorrhage and haemorrhagic transformation, particularly after thrombolysis [50‒52]. The close relationship between CIN and BBB dysfunction may suggest an increased risk in patients with high white matter loads or prior ischaemic infarct.

Aside from neurological disease processes, contrast media have been reported to damage the BBB and, in doing so, facilitate their own passage across the BBB [53]. It has been reported that the severity of BBB disruption is directly proportional to the concentration of contrast, as well as the length of time the cerebrovasculature is exposed to contrast [54]. The mechanism by which this occurs is likely linked to osmolarity, with hyperosmolar agents causing contraction of endothelial cells, leading to separation of the tight junctions [55, 56]. This theory has been confirmed by observation of the BBB under electron microscopy [56]. Nonetheless, damage is likely to be multifactorial, due to the observation of CIN following administration of iso-osmolar agents [57‒59], and it is possible that contrast agents play a less significant role in the actual opening of the BBB.

Other factors, including hypertension and epilepsy, have been suggested to affect BBB integrity. Hypertension may be a key, with its association with CIN confirmed in clinical cohorts [6, 60]. Uncontrolled hypertension leads to increases in shear stress on the cerebral vasculature, possibly leading to BBB damage [61]. As a result, it would be expected that in the context of a patient with such comorbidities, their susceptibility to contrast-induced BBB dysfunction is increased [62].

Clinically, CIN has been observed to manifest following contrast administration in a range of settings, including CT [63], cerebral angiography [4], and coronary procedures [64]. The reported incidence of CIN following cerebral angiography ranges from 0.24 to 3.5% [6, 9, 10, 65]. On the other hand, following coronary angiography, one study reported an incidence of 0.15% [66]. This may suggest that the tissue bed of contrast administration also plays a role in pathogenesis. Current theories include that the transient increase in shear stress following contrast injection causes damage to the BBB of local vessels [2]. Furthermore, in intracranial interventions, navigation and manipulation of endovascular equipment and devices may further exacerbate shear stress, leading to further breakdown in BBB integrity.

Following BBB disruption, neurological complications induced by contrast administration may be due to direct effects of contrast following passage through the BBB. In addition, it is possible that contrast-induced damage to the BBB interferes with the strictly maintained conditions of the CNS, leading to suboptimal neurological function.

Following passage across the BBB, the clinical symptomatology of CIN is thought to be at least partially attributed to the direct chemotoxic effects of contrast in neural tissue [38], with a number of preclinical studies demonstrating the detrimental impact of contrast on the physiological function of neurons (Table 2). Two major theories have been postulated as the underlying mechanisms. The first is the effect of contrast on cellular glucose metabolism. The second is the effect of contrast on the electrophysiological function of nerve cells. The majority of experiments have been conducted in animal subjects, with intrathecal contrast administration. Although these studies do not account for the role of the BBB in endovascular contrast procedures, they may provide insight into the effects of contrast once it has bypassed the BBB.

Table 2.

Summary of preclinical studies

AuthorYearModelContrast typeContrast administrationSalient findings
Bryan et al. [67]  1982 Rat Iohexol, diatrizoate, iothalamate, metrizamide in vitro Iohexol and metrizamide caused inhibition. Sodium diatrizoate and iothalamate caused early excitation and later inhibition 
Bryan and Johnston [68]  1982 Aplysia californica Iothalamate, diatrizoate, metrizamide in vitro Suppression of inhibitory postsynaptic potentials 
Hershkowitz and Bryan [69]  1982 Rat Diatrizoate, metrizamide in vitro Epileptogenic activity. Depression of synaptically evoked fields 
Elkholm et al. [70]  1983 Rat Metrizamide in vitro Inhibited glucose uptake 
Bertoni and Weintraub [71]  1984 Human Metrizamide in vitro Competitive inhibition of hexokinase 
Bryan and Hershkowitz [72]  1984 Rat Diatrizoate, metrizamide in vitro Epileptogenesis from repetitive action potentials, followed by electrical depression secondary to membrane hyperpolarisation 
Hershkowitz and Bryan [73]  1984 Rat Diatrizoate, metrizamide in vitro Epileptogenic activity, followed by depression of action potentials 
Maly et al. [74]  1984 Rabbit Iohexol, metrizamide Intrathecal Metrizamide had excitatory effect. Iohexol had no effect 
Bech et al. [75]  1984 Rat Metrizamide Intrathecal Reduced brain glucose phosphorylation 
Simon et al. [76]  1987 Rat Metrizamide, iohexol, iotrol, iopamidol in vitro Metrizamide competitively inhibited hexokinase, while iohexol, iotrol, and iopamidol had no effect 
Morris et al. [77]  1988 Rat Metrizamide, iohexol, iopamidol in vitro Metrizamide caused reduced carbon dioxide production. Iohexol and iopamidol caused no significant effect 
Elkholm et al. [78]  1989 Rat Metrizamide in vitro Inhibited glucose uptake 
Morris et al. [79]  1989 Rat Iotrol, iodixanol, metrizamide in vitro Metrizamide reduced carbon dioxide production. iodixanol and iotrol increased carbon dioxide production 
Azuma et al. [80]  1989 Rat Metrizamide Intrathecal Slowing of EEG waves in the cortex, hippocampus, and thalamus. Reduced glucose transport 
Ekholm et al. [81]  1990 Rabbit Iodixanol, iohexol, metrizamide Intravenous Iodixanol and metrizamide caused significant decreases in deoxyglucose uptake. Iohexol had no effect 
Cicciarello et al. [82]  1990 Rat Iohexol, iopamidol, metrizamide Intrathecal Reduction in metabolic activity with metrizamide. No effect with iopamidol or iohexol 
Sundgren et al. [83]  1995 Rabbit Iodixanol, iohexol, iotrolan Intrathecal Excitatory effects and seizure activity following iodixanol and iotrolan. Depressive effect following iodixanol, iohexol, and iotrolan 
Maly et al. [84]  1995 Rabbit Iodixanol, iopamidol, iotrolan Intrathecal Seizure activity observed with iopamidol and iotrolan. Focal twitching observed with iodixanol 
AuthorYearModelContrast typeContrast administrationSalient findings
Bryan et al. [67]  1982 Rat Iohexol, diatrizoate, iothalamate, metrizamide in vitro Iohexol and metrizamide caused inhibition. Sodium diatrizoate and iothalamate caused early excitation and later inhibition 
Bryan and Johnston [68]  1982 Aplysia californica Iothalamate, diatrizoate, metrizamide in vitro Suppression of inhibitory postsynaptic potentials 
Hershkowitz and Bryan [69]  1982 Rat Diatrizoate, metrizamide in vitro Epileptogenic activity. Depression of synaptically evoked fields 
Elkholm et al. [70]  1983 Rat Metrizamide in vitro Inhibited glucose uptake 
Bertoni and Weintraub [71]  1984 Human Metrizamide in vitro Competitive inhibition of hexokinase 
Bryan and Hershkowitz [72]  1984 Rat Diatrizoate, metrizamide in vitro Epileptogenesis from repetitive action potentials, followed by electrical depression secondary to membrane hyperpolarisation 
Hershkowitz and Bryan [73]  1984 Rat Diatrizoate, metrizamide in vitro Epileptogenic activity, followed by depression of action potentials 
Maly et al. [74]  1984 Rabbit Iohexol, metrizamide Intrathecal Metrizamide had excitatory effect. Iohexol had no effect 
Bech et al. [75]  1984 Rat Metrizamide Intrathecal Reduced brain glucose phosphorylation 
Simon et al. [76]  1987 Rat Metrizamide, iohexol, iotrol, iopamidol in vitro Metrizamide competitively inhibited hexokinase, while iohexol, iotrol, and iopamidol had no effect 
Morris et al. [77]  1988 Rat Metrizamide, iohexol, iopamidol in vitro Metrizamide caused reduced carbon dioxide production. Iohexol and iopamidol caused no significant effect 
Elkholm et al. [78]  1989 Rat Metrizamide in vitro Inhibited glucose uptake 
Morris et al. [79]  1989 Rat Iotrol, iodixanol, metrizamide in vitro Metrizamide reduced carbon dioxide production. iodixanol and iotrol increased carbon dioxide production 
Azuma et al. [80]  1989 Rat Metrizamide Intrathecal Slowing of EEG waves in the cortex, hippocampus, and thalamus. Reduced glucose transport 
Ekholm et al. [81]  1990 Rabbit Iodixanol, iohexol, metrizamide Intravenous Iodixanol and metrizamide caused significant decreases in deoxyglucose uptake. Iohexol had no effect 
Cicciarello et al. [82]  1990 Rat Iohexol, iopamidol, metrizamide Intrathecal Reduction in metabolic activity with metrizamide. No effect with iopamidol or iohexol 
Sundgren et al. [83]  1995 Rabbit Iodixanol, iohexol, iotrolan Intrathecal Excitatory effects and seizure activity following iodixanol and iotrolan. Depressive effect following iodixanol, iohexol, and iotrolan 
Maly et al. [84]  1995 Rabbit Iodixanol, iopamidol, iotrolan Intrathecal Seizure activity observed with iopamidol and iotrolan. Focal twitching observed with iodixanol 

Glucose Metabolism

Disruption to neural glucose metabolism can lead to significant neurological dysfunction, as the CNS relies almost entirely on glucose to fuel cellular function [78, 85]. Following contrast administration, several animal studies have reported an overall reduction in cerebral glucose consumption [70, 77]. The leading explanation for this relates to the action of iodinated contrast as a competitive inhibitor to hexokinase, an enzyme that plays an essential role in cerebral glucose metabolism [70, 71, 76, 77, 86]. Another factor that may contribute to metabolic dysfunction is the reported reduction in net glucose transport into cells following contrast administration [80]. Overall, disrupted cellular metabolism likely plays a significant role in the underlying pathophysiology of CIN, with neurons unable to function effectively or efficiently without the ability to meet their metabolic requirements.

Neuron Electrophysiology

Electrical activity within normal limits is central to the role of the neuron, and deviation from normal electrophysiology has significant ramifications on neurological function. Contrast agents have been demonstrated to interfere with the electrical activity of neurons, with several studies reporting inhibition of action potentials linked to contrast administration [67]. This is likely explained by disruptions to the neuron action potential as a result of progressive hyperpolarization of the resting membrane potential [67‒69, 72]. Neuron hyperpolarization increases the action potential threshold, resulting in an overall inhibitory effect [87]. Consequently, contrast agents that induce excessive hyperpolarization may suppress electrical activity. However, on the other hand, several preclinical studies have also observed epileptogenic neural activity in response to contrast administration [68, 74, 83, 88]. The reasons for this are not clear, although it is likely responsible for the seizure activity observed in CIN.

Overall Effects

Of the two proposed mechanisms, it is not clear which theory is primarily responsible for the neurotoxic effects of contrast, whether it be impaired glucose metabolism, neuroelectric disruption, or a combination thereof. It may be that these processes are interrelated, with a disturbance in neuron metabolism leading to neurophysiological sequelae.

The chemical structure of contrast agents may also play a role in the severity of neurological disruption experienced. Wible et al. [89] demonstrated that low hydrophilicity of contrast media was associated with a larger degree of neurotoxicity. The inverse relationship between water solubility and neurotoxicity is likely explained by the reduced permeability of water-soluble agents across the phospholipid cell membrane. Even if across the BBB, agents unable to pass through the cell membrane are less likely to induce toxic effects. This may be a clinically relevant consideration for future practice.

As aforementioned, it has been reported that the severity of BBB disruption is directly proportional to the concentration of contrast, as well as the length of time the cerebrovasculature is exposed to contrast [54]. Clinically, however, there have been reports of CIN with as little as 18 mL of contrast administered [90]. Ongoing investigation is required in the clinical context to clarify if a dose-dependent relationship does in fact exist.

Limitations of Preclinical Literature

Ultimately, the mechanisms of contrast neurotoxicity at a cellular level require continued investigation, with a lack of contemporary studies in the literature, and the majority of studies being conducted between 1980 and 2000. Additionally, despite a variety of contrast agents currently in use, only a small subset has been studied. In particular, metrizamide is less clinically relevant in current practice, having been withdrawn by the FDA in 2021, although the conclusions drawn from studies utilizing it still provide insight. Preclinical experiments may benefit from the examination of more contrast agents, including the growing range of available options. In addition, the vast majority of studies have been conducted in animal cohorts with contrast doses that are not clinically realistic. Furthermore, most studies were in vitro or administered contrast intrathecally, which disregards the role of the BBB in intravascular contrast administration. Despite the shortcomings, these preclinical studies may provide some insight into the possible mechanisms of neurotoxicity, particularly once contrast media have bypassed the BBB.

The clinical presentation of CIN has also been linked to cerebral oedema. Radiological reports have demonstrated sulcal effacement and cerebral oedema in CIN patients [2, 91]. The mechanisms behind these findings may be twofold. Firstly, breakdown of the BBB may lead to vasogenic oedema, allowing the passage of solutes and fluid across a once impermeable membrane. This is radiologically confirmed with vasogenic oedema on MR imaging [92]. Secondly, without an intact BBB, hyperosmolar contrast media are free to extravasate, leading to a shift in the oncotic pressure gradient, further contributing to cerebral oedema. The symptoms of CIN, therefore, may be caused by the direct dysfunctional effects of cerebral oedema or may be a result of the compression of neural structures in the setting of raised intracranial pressure [12]. Consequently, many authors have reported the use of mannitol in the treatment of CIN [11, 93‒95]. Although not confirmed, it is theorized that by alleviating the intracranial pressure caused by cerebral oedema, the symptoms of CIN will also be minimized. Moreover, cerebral oedema may be linked to an increased severity CIN manifestation, with cases of mortality being linked to a rise in intracranial pressure to fatal levels [7]. Further investigation analysing intracranial pressure data in CIN patients may serve to elucidate this relationship.

CIN remains a poorly understood clinical entity, with little evidence base regarding diagnosis and treatment. This is particularly concerning following neurointerventional procedures, where ischaemic stroke is a known complication. An improved understanding of the pathophysiological mechanisms underlying CIN may provide insight into diagnostic decision-making, streamline investigations and prevent unnecessary interventions.

The clinical manifestation of CIN is heterogenous. Common symptoms in the reported literature include impaired GCS, confusion, cortical blindness, seizures, and motor/sensory deficit [8]. A number of these symptoms may be explained by impaired metabolism and inhibition of electrophysiology of neurons, as postulated by several preclinical studies. Seizure activity, in particular, is likely to be closely linked to the changes in electrophysiology. Nonetheless, the relationships between cellular neurotoxicity and the clinical manifestation of CIN have not been thoroughly examined, and therefore limit the extent of practical conclusions that can be drawn. Further clinical investigation, including radiological findings and symptoms, as well as other investigations such as electroencephalography, may provide significant insight into the mechanisms underlying CIN. Comparison between the physiological and clinical findings of CIN would further improve understanding of CIN as a clinical entity. Unfortunately, in the current literature, there is a paucity of studies directly comparing the pathophysiology of contrast neurotoxicity with its clinical manifestations.

The radiological findings associated with CIN remain unclear. Some have reported subarachnoid contrast staining/hyperattenuation which would support the notion of contrast extravasation through a dysfunctional BBB [96‒98]. Unsurprisingly, cerebral oedema is reported on the basis of radiological findings. Importantly, vasogenic oedema has also been reported which is in keeping with the notion of BBB breakdown [92]. Nonetheless, many have reported both CT and MR imaging absent of abnormalities [6, 10, 97, 99], ultimately demonstrating the need for further investigation into the radiological considerations of CIN.

In the planning phase, when assessing the risk of CIN preoperatively, several factors should be taken into account. Comorbidities, most notably hypertension, prior ischaemic stroke, and structural neurological pathologies, have been suggested to increase the risk of BBB damage, which may exacerbate the effects of contrast. Clinical investigation in a cohort of neurointerventional patients has demonstrated an increased risk of CIN in uncontrolled hypertension [60]. In addition, radiological evidence of small vessel disease may provide some prognostic value, although this remains to be proven clinically. Ultimately, the current literature suggests that a thorough consideration of factors may be important in preventing the occurrence of CIN.

Procedural factors should also be considered in the preoperative setting, including procedural indications, technical difficulty, and approach, all of which may dictate the volume of contrast used, as well as the time exposed to contrast, which have been suggested to be linked to BBB damage [54]. Unlike chronic comorbidities which are difficult to effectively control, procedural factors may be more easily adjusted. As with any intervention, careful consideration of risks and benefits of technical options should dictate the eventual operative decisions. Finally, the osmolarity of contrast may affect the degree of BBB breakdown, although this is less clinically relevant in contemporary practice.

Future investigation into the underlying pathophysiology of CIN is certainly warranted. Preclinical studies utilizing the growing range of contemporary contrast agents will improve the relevance of current pathophysiological knowledge. Direct comparisons between clinical findings and pathophysiology will also enhance overall understanding of CIN as a clinical entity. Clinical data on the relationship between cerebral oedema and CIN is lacking. A study into the trends in intracranial pressure values may provide valuable insight, particularly regarding implications for clinical management. Furthermore, clinical studies in patients who have suffered from CIN should be conducted to further clarify risk factors, which will directly improve decision-making.

The pathogenesis of CIN appears to be multifactorial. A key step appears to be the degradation of the BBB, due to a variety of factors including uncontrolled hypertension, prior stroke, and possibly the contrast agents themselves. Once across the BBB, contrast agents may exert neurotoxic effects, as well as lead to cerebral oedema due to changes in oncotic pressure gradients. Ultimately, ongoing investigation is required to increase clarity surrounding this poorly understood complication.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

F.P.M., L.L., T.G., and L.-A.S. contributed to the conception and design of the work. F.P.M., L.L., J.M., R.C., T.G., A.J.P., and L.-A.S. contributed to the acquisition, analysis, and interpretation of data for the work. F.P.M. drafted the work, and L.L., J.M., R.C., T.G., A.J.P., and L.-A.S. critically revised it. All authors gave final approval of the version to be published and agreed to be accountable for all aspects of the work.

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