Delayed non ischemic cerebral enhancing lesions after endovascular stent assisted coiling of an unruptured intracranial aneurysm, a case description followed by a literature analysis on the probable causes, differential diagnosis and treatment

Introduction

Endovascular treatment is considered the first-line treatment for intracranial aneurysms. The International Subarachnoid Hemorrhage Trial (ISAT trial) (1) showed that endovascular coiling was more likely to result in independent survival at 1 year post procedure compared to neurosurgical clipping for ruptured intracranial aneurysm patients. Intravascular aneurysm coiling also result in a generally shorter length of hospital stay and lower overall treatment cost than surgical clipping (2). Most physicians recommended endovascular treatment as their first-choice management for most ruptured (78%) and unruptured (71%) aneurysms in a survey conducted in the United States (3). Endovascular coiling carries the risk of several complications, most commonly intraprocedural aneurysm rupture and thromboembolic ischemic infarcts (4). Delayed non ischemic cerebral enhancing (NICE) lesions (5) is a rare complication of endovascular treatment, it is also known in the literature as delayed enhancing lesions (6), delayed multiple white matter lesions (7), delayed intracranial parenchymal changes (8) and delayed leukoencephalopathy (DLE) (9). This complication is characterized by the appearance of contrast enhancing lesions on magnetic resonance imaging (MRI) in the white matter regions of the territory perfused by the artery that received endovascular treatment, usually two weeks or more after the procedure (9). In this article, we will refer to this condition as delayed NICE lesions as we believe it to be the most descriptive term for this complication. In the last two decades, there have been scattered reports of this rare complication. This article describes the first case encountered at our tertiary level university hospital. We provide a brain computed tomography (CT) image and three MRI image sets, each done at three different time points with 5 sequences each, showing clearly the characteristics of this complication on imaging and its progress with treatment. We review the literature and describe the epidemiology and demographic of delayed NICE lesions. We then discuss the possible causes, pathophysiology and risk factors of this complication and further analyses the most probable cause in our patient. Delayed NICE lesions has an extensive list of possible differential diagnosis such as cerebral infection, delayed post hypoxic leukoencephalopathy (DPHL), cerebral autoimmune vasculitis, autoimmune encephalitis etc. We provide a discussion on the most likely differential diagnosis such as cerebral infection and DPHL. As our team initially highly suspected cerebral infection, we briefly discuss the similarities and differences of our case MRI images compared to the typical MRI images of our most suspected cerebral infections [intracranial tuberculosis (TB), cysticercosis, toxoplasmosis and schistosomiasis]. We also discuss the similarities and differences on clinical presentation and imaging of DPHL and delayed NICE lesions. A diagnostic workup to help clinician manage patients with suspected delayed NICE lesions and a brief description of reported treatment regimen is also included.

Case presentation

A 54-year-old women of Han Chinese ethnicity went to a county hospital complaining of dizziness. Because of a suspected aneurysm on brain computed tomography angiogram (CTA), digital subtraction angiography (DSA) was performed and an aneurysm of around 2 mm in diameter was found in the supraclinoid segment of the left internal carotid artery (ICA) (Figure 1A). Due to the small size of the aneurysm, she was not recommended endovascular treatment but monitoring at regular intervals. Eight months later, the patient went back to the county hospital and requested hospitalization and review of the aneurysm. A review DSA was performed and showed no change in the aneurysm. The patient was anxious about the potential risk of this aneurysm and requested endovascular treatment. She was otherwise asymptomatic, in good general condition, denied suffering from any chronic illnesses, food or drug allergies. Nothing particular was noted on physical and neurological exam. Stent assisted aneurysm coiling was performed under general anaesthesia. The procedure lasted around one hour and thirty minutes, materials used for the intervention are shown in Table 1. The procedure was uneventful and post coiling DSA showed proper placement of the coils. Post-operative CT scan showed no intracranial bleeding or contrast leakage. At discharged, the patient was suffering from no immediate post operative complications, neurological functions were intact and there was no bleeding seen at the puncture site. She was discharged on aspirin, clopidogrel and atorvastatin. Twenty-two days after the procedure, patient came back to the emergency department of the county hospital complaining of gradually worsening weakness and decreasing grip strength in her right upper limb, unsteady gait and slurred speech for 8 days. She was conscious with normal cognitive function. Physical examination showed right upper limb muscle strength of grade three with normal muscle tone. Left upper limb muscle strength was normal. No obvious abnormalities were found in bilateral lower limbs. No obvious abnormalities were found on other neurological physical examination. Her blood pressure was 130/89 mmHg. Emergency brain CT scan (Figure 1B) showed patches of low-density shadows in the left hemisphere, without any intracranial bleeding, midline shift or changes in shape, size and position of the ventricles. She received a provisional diagnosis of acute ischemic stroke and was transferred to our hospital for admission. She was placed under the care of the Department of Neurosurgery. The patient continued to take aspirin and atorvastatin as before, while clopidogrel was replaced by ticagrelor. The patient was put on the free radical scavenger edaravone, mannitol (125 mL/25 g twice per day for 2 days) and dexamethasone (10 mg, intravenous drip, once a day for two days in total). The weakness of her right upper limb did not improve but progressively got worse. A brain MRI plain scan + contrast enhanced was performed (Figure 2A,2B), which showed patchy anomalous areas in the white matter of the left frontal, temporal, occipital and parietal lobe. The areas were hypointense on T1weighted sequence, hyperintense on T2 weighted sequence, hyperintense on fluid-attenuated inversion recovery (FLAIR) and hyperintense on apparent diffusion coefficient (ADC) mapping. No obvious high signal region was seen on diffusion weighted imaging (DWI). Small nodular lesions were found scattered within the anomalous patchy areas, they were hypointense on T1 and DWI with an isointense rim, isointense on T2 and Flair, and highly enhanced on T1 after contrast administration. She was then transferred to our department of Neurology for further management after seven days in the neurosurgical ward. On the first day in the neurology ward, the patient showed fatigue with impaired cognitive function and dysarthria. The muscle strength grading of the right upper limb was zero. Muscle strength grading of her right lower limb was 1 with decreased muscle tone. National Institute of Health Stroke Scale (NIHSS) score was 12, Babinski sign was positive on the right side but negative on the left side with negative meningeal irritation sign. Based on the MRI images and neuroradiologist suggestion, we suspected cerebral infection with organisms such as TB, cerebral parasitic disease (e.g., cysticercosis, toxoplasmosis or schistosomiasis) or autoimmune encephalitis. she was put on antibiotics (ceftriaxone, tazobactam and levofloxacin). Lumber puncture was performed and cerebrospinal fluid (CSF) was clear, abnormal CSF laboratory results were: elevated protein, albumin, chloride and immunoglobulin G (IgG). CSF smear pathological report showed cytological changes suggestive of small lymphocyte reaction, CSF was thoroughly screened for pathological organisms, all results were negative. Feces was tested for parasite eggs and fungi with negative results.

Figure 1 Patient’s DSA image immediately after aneurysm coiling and her emergency CT image performed when she presented at the local hospital due to neurological symptoms. (A) DSA image, with the red arrow showing an aneurysm of around 2 mm in the supraclinoid segment of the left internal carotid artery, no blood flow into the aneurysm sac can be seen. (B) CT scan showing patches of low density shadows in the left frontal, temporal, parietal and occipital lobes. CT, computed tomography; DSA, digital substraction angiography.

Figure 2 Patient’s MRI images that were performed at three different timepoints, showing the characteristics of this condition and its progress with treatment. (A,B) First MRI scan series performed 13 days after start of symptoms and 27 days after the aneurysm coiling shows nodular lesions surrounded by areas of edema in the left frontal, temporal, occipital and parietal lobe. On T1, the nodular lesions appear hypointense with an isointense rim surrounded by a hypointense area that represent edema. On T2, lesions appear isointense, surrounded by hyperintense edema region. No area of higher diffusion restriction can be seen on DWI. High intensity signal region corresponding to the edema can be seen on FLAIR. The nodular lesions are highly enhancing on T1 post contrast. Of interest, a nodular lesion with a central dot can be seen in the left parietal lobe on T2 and ADC, this lesion is hypointense with an isointense rim on T1, it is isointense on ADC with a hyperintense central dot. (C,D) Second MRI performed 17 days after the first MRI and 12 days after starting steroid pulse therapy showing a decrease in the number of nodular lesions. A decrease in the size of the peripheral edema region can also be seen. The lesions no longer enhance on T1 post contrast. (E,F) The third MRI scan performed 2 months after the second and 2 months and a half after the start of steroid pulse therapy shows a large decrease in size of the perilesional edema region. The number of nodular lesions has decreased on all MRI sequences and edematous areas are no longer visible on post contrast T1. The figures (A,C,E) showed the slice at the level of centrum semiovale, while the others (B,D,F) showed the slice at midbrain. ADC, apparent diffusion coefficient; DWI, diffusion weighted imaging; FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging.

Blood eosinophil count and serum interleukin-6 (IL-6) were elevated. Blood heparine binding protein was highly elevated at 37.7 ng/mL, pointing to possible vascular leakage and vasogenic edema.

All blood and serum investigation for pathogenic organisms and autoimmune diseases were negative. The details of all laboratory test sent and results can be found in Tables 2,3. We suggested patient to do a brain biopsy but she refused.

As patient’s condition was getting worse on current medications, based on a thorough diagnosis workup with respect to her clinical symptoms, imaging findings and lab results, a diagnosis of “Delayed non ischemic cerebral enhancing lesions following endovascular treatment” was made.

Methylprednisolone (120 mg, intravenous, once per day, for 5 days) was started five days after the patient’s transfer to our ward.

She responded positively to the steroid regimen. Three days after the start of methylprednisolone treatment, she could slightly move her upper right limb on the bed (muscle strength grading 1) with improved cognitive function in memory domain. After five days of treatment, her orientation and memory function improved a lot with clear speech. Muscle strength in her right upper limb and right lower limb improved to grade 2 and grade 3, respectively. Muscle tone in right limbs were still weakened. Babinski sign was positive on the right side and negative on the left side. The patient was discharged on oral prednisolone 60 mg daily.

One week after discharge, she came to our outpatient clinic for follow up. Her symptoms greatly improved. Cognitive function was good with no dysarthria. Muscle strength in right upper and lower limbs was grade 5. Gait was steady with no difficulty ambulating. Blood tests showed a decreased Eosinophil count, C-Reactive protein and IL-6 (Table 4). A follow up MRI (Figure 2C,2D) 12 days into steroid treatment and 17 days after the first MRI showed a decrease in the number of nodular lesions and a decrease in the size of the peripheral edema region. The lesions no longer enhanced on T1 post contrast.

She was asked to taper her oral prednisolone by reducing 10 mg every week until 20 mg which was then kept until next follow up.

Two months after discharge, a follow up MRI (Figure 2E,2F) showed only small patchy hyperintensities on T2 and Flair in the left frontal and parietal lobe. The patient was asked to keep oral prednisolone at 20 mg daily for one more month and then reduce to 10mg daily thereafter for 3 months (i.e., steroid treatment for 6 months in total).

Four months after discharge, the patient came back to our clinic for review and showed a complete recovery. She demonstrated good cognitive function and scored 23/30 on Montreal Cognitive Assessment (MoCA) score and 28/30 on Mini-Mental State Examination (MMSE). NIHSS score was 0 and Barthel scale score was 100.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Epidemiology and demographics

Delayed NICE lesions is a relatively rare complication of endovascular therapy and very few studies have been performed to estimate its incidence following endovascular procedures. Delayed NICE lesions has been reported following endovascular aneurysm coiling (5-12), non-coil embolization flow diverter stent (10,13-16), mechanical thrombectomy (17,18) and diagnostic DSA (17). A retrospective single center study (18) analysing 7,446 endovascular procedures (both diagnostic and therapeutic) found an incidence of 0.14% for symptomatic delayed NICE lesions, the incidence rose to 0.45% if only therapeutic procedures were accounted for and to 1.02% if only procedures involving placement of intracranial devices are taken into account. This study (18) reported a highest incidence of 1.66% among patient that underwent aneurysm embolization. A single center study (9) analysing 1,754 endovascular aneurysm coiling procedures found the incidence of delayed NICE lesions (both symptomatic and asymptomatic) to be 0.9%. An incidence of 0.05% was reported by a retrospective multicenter study analysing 58,815 intracranial aneurysm endovascular treatment procedures performed over 13 years (19). Another study involving 746 patient that underwent endovascular aneurysm treatment (10) reported an incidence of 0.67%. A much higher incidence of 2.3% was found by a study involving 305 patient that underwent treatment only for unruptured aneurysm (8). From a systematic review of the literature published in 2021 (11) that reviewed 17 articles, most patients suffering from delayed NICE lesions after intracranial aneurysm repair were female, with a median age of 54 (range, 36–65; average 53±8.16) years. The time between procedure and the appearance of symptoms ranged from 14 and 510 days. However, one case report (20) described symptoms starting after only 4 days and another case series (12) reported cases that had delayed symptoms onset of up to 4 years post procedure (the longest reported so far). Some (30%) cases are asymptomatic at the time of diagnosis (11).

Possible causes and pathophysiology

Delayed NICE lesions following neuroendovascular procedure is suspected to have multiple etiologies such as, foreign body emboli of hydrophilic polymer coatings from the inner lumen of catheters (5,6,12,14,16,20-22), Nickel allergy (7,8), embolisation of coil materials (15,23) excessive immune reaction to polyglycolic acid/lactide polymer (PGLA) containing coils (24) and contrast induced encephalopathy (9).

Foreign body polymer microemboli is one of the suspected cause of delayed NICE lesions following endovascular procedures. Foreign body embolization during neuroendovascular intervention was first reported by Barnwell et al. in 1997 (25). Using in vitro tests, the authors demonstrated peeling of hydrophilic coating particles from the surface of a microcatheter. They found the same type of material in brain tissue samples taken from patients that unfortunately passed away after neuroendovascular treatment (25). Another author (6) performed bench-top analyses and found whitish semitransparent material adherent to the inner lumen of a microcatheter that was retrieved and dissected following unusual friction during aneurysm coiling and similar material was sieved when the procedure was simulated in vitro with multiple coil advancement and withdrawal maneuvers within an acutely angulated microcatheter (6). It is suspected that during long, complex and difficult endovascular interventions on patients involving tortuous difficult to navigate vessels, particulate materials may be sheared off the inner lumen of catheters. These particles then causes foreign body microemboli in the region supplied by the main artery catheterized during the intervention (11). Type IV granulomatous immune reaction to the foreign bodies then causes the clinical symptoms and contrast enhancing lesions surrounded by edema seen on MRI (12). This hypothesis is supported by the observation that the vast majority (6-17) of reported cases of NICE lesions following neuroendovascular therapy shows lesions location being restricted mostly to the area supplied by the major vessel catheterised during the procedure (for example the vessel containing the aneurysm being treated). Our patient also showed lesions restriction mostly to the white matter regions supplied by the left ICA, correspondingly, the treated aneurysm was located in the supraclinoid segment of the left ICA. In our patient, the involvement of part of the occipital lobe may be due to foreign particle emboli via the posterior communicating artery. Delayed NICE lesions being positively associated with longer fluoroscopy duration and larger amount of contrast use (9) also support this foreign body emboli hypothesis by suggesting that longer more difficult procedures are of higher risk possibly due to increased friction between the materials used during the procedure, resulting in shedding of a larger amount of foreign particles. A systematic review published in 2016 (22) that analyses 32 patients with confirmed intracranial polymer induced reaction (by histopathology) after endovascular procedures found that 12 patients (38%) experienced delayed enhancing parenchymal lesions in the region supplied by the artery that undergone treatment. The lesions occurred weeks to months following the procedure. According to the authors (22) own experience, Delayed and persistent enhancing lesions may represent the most specific radiologic pattern of polymer embolisation.

Several articles have described brain tissue biopsy taken from patients suffering from delayed NICE lesions (12,14,17,21,23). The biopsy findings were described as “granulomatous angiitis surrounding amorphous foreign material, identical in staining characteristics to the coating of the guiding catheter” (21), “non-polarizable foreign material surrounded by multinucleated foreign body type macrophage inside a small meningeal vessel” (14), “non-specific reactive changes with granulomatous inflammation”, “perivascular lymphocyte infiltration” (17) and “nonrefractile filamentous blue-gray foreign body material found within some granulomas and microabscesses” (23). Similarly to our patient, these patients all showed multiple nodular enhancing lesions on post contrast T1 MRI scan. We did not perform any biopsy on our patient because of the invasive nature of the test and her recovering completely following treatment but biopsy may be warranted in difficult cases not responding to medical treatment. Biopsy of the lesion is probably the gold standard to establish with certainty the cause of this complication and in our case, as we did not take any tissue sample for histopathological test, we cannot say with certainty that foreign body microembolism was behind our patients lesions. However, we personally believe that immune reaction to foreign body emboli was the most probable cause of her delayed NICE lesions.

Nickel allergy is also thought to be a possible cause of delayed NICE lesions following endovascular interventions (5,7). Many intracranial stents are made out of Nitinol, an alloy composed of 55% Nickel and 45% Titanium. In one published case report (7), a patient suffering from delayed NICE lesions after stent assisted coiling of an unruptured aneurysm has shown a positive reaction to Nickel on a skin allergy test. It has been shown that nickel is released in the blood after the use of nickel containing devices (26), the concentration of nickel gradually rises after implantation of the device, peaks at one month after the procedure then comes back to baseline level after one year. After prolonged contact with the bioenvironment, a stable coating of nickel oxide and calcium phosphate form on the stent, preventing further release of nickel ions into the blood. The patient described in this case report (7), even though she shown a positive allergic skin reaction to nickel, was not mentioned to have undergone a post-contrast MRI scan. Post contrast MRI scan could have shown further information such as possible presence of enhancing nodular lesions. The patients’ lesions were also in the vascular territory perfused by the parent artery of her aneurysm. A biopsy to rule out foreign body emboli was not performed on this particular patient (7). Nevertheless, we cannot totally exclude that nickel allergy could have caused or contributed to the pathogenesis of delayed NICE lesions in this patient. In a retrospective study published in February 2020 (9), of 16 patients suffering from delayed NICE lesions after aneurysm coiling, skin patch allergy test to metals commonly use in endovascular treatment were performed on seven of the patients, none were found to be allergic to nickel. Due to Nickel ions being extremely small compared to particulate matter sheared off catheters, It can be presume that allergy to nickel would cause a much larger area of the brain and possibly other bodily system to be affected compared to the lesions being primarily restricted to only the area perfused by the main artery where the intervention took place. Delayed NICE lesions also occurred after several endovascular procedures performed without implantation of any nickel containing devices such as aneurysm repair using coiling alone (not stent assisted, no nitinol coils used) (17,24), flow diverter stent not containing nitinol (Pipeline™, Covidien, Dublin, Ireland) (14), mechanical thrombectomy (17,18) and diagnostic DSA only (17). The LEO+ self-expanding stent (Balt EXTRUSION SAS, Montmorency, France) used in our patient is made up of Nitinol. The Wallaby Esperance™ Distal access catheter (Wallaby Medical, Shanghai, China) also contains Nitinol but we did not perform any skin allergy test for metal on our patient, so we do not know if she is allergic to nickel and as such, the possibility of allergy to Nickel to have cause or contributed to our patient’s lesions cannot be rule out.

Embolisation of foreign body particles from coils has also been a proposed as a possible explanation for the pathogenesis of delayed NICE lesions (15,23). Several reported cases showed low signal on susceptibility weighted imaging (SWI) in the area of the lesions (9,15). This is thought to be the result of deposition of microembolic paramagnetic materials from the coils used for aneurysm treatment (15). A case reported by Fealey et al. (23) described contrast enhancing lesions 9 months following coiling of an internal carotid artery aneurysm using bioactive coils, “nonrefractile filamentous blue-gray foreign body material within some granulomas and microabscesses” was found on biopsy. The author stretched, dissected and exposed the polymer filament core of a sample of the coil that was used in the affected patient. Segments of the filament core was stained and analysed under microscope and was found to be indentical to the particles found within the granulomas seen on biopsy. They hypothesized that the repetitive scraping of coils against one another due to pulsatile arterial blood flow may cause dislodgement of multiple small polymer particles over time, these particle moves downstream from the aneurysm causing microemboli, granuloma formation and the characteristic contrast enhancing lesions with peripheral edema seen on imaging. Only bare platinium coils were used on our patient so we can exclude the possibility of polymer materials from the coil being the culprit. The MRI scans performed on our patient did not include SWI sequence and as such, we cannot ascertain on the possible presence of para magnetic materials in her lesions.

Allergy to PGLA containing coils is also a suspected cause of delayed NICE lesions. Localised hypocomplemental vasculitis caused by delayed hypersensitivity reaction to PGLA was suspected to be a cause in one reported case (24). The patient shown a positive result to a PGLA solution mixed with petroleum jelly on a skin patch allergy test. The authors of another case series reporting 2 patients that suffered from delayed NICE lesions after treatment with PGLA containing coils (27) hypothesized that delayed NICE lesions may be due to an exaggerated post operative extravascular inflammatory reaction to PGLA coils. However, neither author (24,27) performed any biopsy on their patients to rule out alternative causes. A retrospective (9) study that analysed 1,722 endovascular coiling procedures with or without delayed NICE lesions failed to show any association between the use of PGLA coils and higher odds of developing delayed NICE lesions. Delayed NICE lesions has also been reported in multiple cases without the implantation of any PGLA containing coils such as coiling with bare platinium coil alone (7,9), use of flow diverter only (10,13,14,16), mechanical thrombectomy (17,18) and diagnostic DSA alone (17). Grewal et al. (20) reported a case of delayed NICE lesions following coiling with PGLA containing coils and subsequently performed an allergy skin test by implantation of bare PGLA, a piece of PGLA containing coil and a piece of bare platinium coil subcutaneously with the patient being off immunosuppressant. After 2.5 weeks, no immune reaction was found to the implanted materials. Our patient underwent stent assisted coiling with NUMEN™ MicroFinish coils (Microport Neurotech Shanghai Co., Ltd., Shanghai, China), these are bare platinium coil without any PGLA content, thus we can exclude allergy to PGLA as a possible cause of her lesions.

Contrast induced encephalopathy (CIE) has also been hypothesize to be a possible cause of delayed NICE lesions. The retrospective study done by Ikemura et al. (9) showed delayed NICE lesions development after endovascular aneurysm coiling to be positively associated with larger than average amount of contrast usage. The authors of a case report (28) describing a patient presenting with typical delayed NICE lesions in the areas supplied by the left middle cerebral artery (MCA) four weeks after coiling of a incidentally found unruptured left ICA aneurysm hypothesized that contrast leakage and toxicity may have been responsible. The patient described in the case report was found on CT to have hyperdense area in the frontal lobe cortex immediately after the coiling procedure. She did not show any neurological deficit immediately after the procedure and was discharged 3 days after coiling. We do not believe CIE to be a cause of delayed NICE lesions as the vast majority of reported cases in the literature did not mention any sign of contrast leakage on post intervention CT scan, which is usually performed to check for bleeding after every endovascular treatment procedure performed under general anaesthesia (such as aneurysm repair). Our patient post-operative CT also showed no sign of contrast leakage. The clinical presentation of CIE is also very different from delayed NICE lesions. CIE usually present less than 24 hours after endovascular procedure (29) and usually present as contrast staining and cerebral edema on CT, symptoms usually resolves within 72 h post-op.

As we did not performed any biopsy of our patient’s lesion and also did not perform any allergy testing, we cannot be certain of the cause or causes of the lesions in our patient. However, the patient’s positive response to steroid, elevated CSF IgG and albumin and CSF smear showing signs of reactive lymphocytic pleocytosis do point out to an inflammatory immune mediated pathogenesis.

Risk factors

A retrospective study (9) that analysed 1,754 endovascular coiling procedures with and without delayed NICE lesions found the condition to be positively associated with longer intraprocedural fluoroscopy duration, larger than average amount of contrast usage and the use of a larger number of micro catheters, this suggest longer, probably more complex (use of a larger number of endovascular materials) and difficult procedures (tortuous vessels) being of higher risk.

In a single center retrospective study analyzing 7,446 endovascular intervention (18), 11 cases of delayed NICE lesions were found (incidence of 0.14%). Ten resulted from aneurysm repair and one from mechanical thrombectomy, suggesting that endovascular aneurysm treatment carries a higher risk. This same study found the highest incidence of 1.66% if only aneurysm treatment procedures are used to calculate incidence.

Differential diagnosis

On imaging, delayed NICE lesions are characterized by abnormal signals on MRI restricted to the white matter areas supplied by the main artery that host the pathology (for example aneurysm) that received endovascular treatment. The lesions are usually hypointense on T1, hyperintense on T2 and FLAIR, no high signal is usually seen on DWI for cases without ischaemia such as aneurysm treatment. On contrast administration, highly homogeneously enhancing granular lesions can be observed within the abnormal signal areas seen on T1 and T2 (9-11).

On imaging, the most likely differential diagnosis is cerebral infection with bacteria such as TB or parasites such as cysticercosis, toxoplasmosis or schistosomiasis. Autoimmune encephalitis, autoimmune vasculitis and DPHL are also possible non infectious differentials. As our team and neuroradiologists initially highly suspected cerebral infection to be the diagnosis, we will briefly describe the main similarities and differences between our patient’s lesions compared with the typical presentation of our most suspected pathogenic organisms on MRI.

On imaging, delayed NICE lesions can be mistaken for intracranial TB, especially the parenchymal form. Parenchymal cerebral TB most often manifest as tuberculous granuloma (30). The granuloma can occur as a single lesions or as multiple relatively small scattered granulomatous lesions often referred to as miliary TB. Mycobacterium TB reaches the brain by hematogenous dissemination and the granulomatous lesions are most commonly observed at corticomedullary junctions and periventricular regions (30). The appearance of our patient lesions on post contrast T1 can bear some resemblance to miliary cerebral TB. Miliary cerebral TB also shows multiple highly enhanced lesion scattered within the brain parenchyma on post contrast T1 images. The main difference is that our patient shows lesion only on the left hemisphere whereas miliary TB often affect both hemisphere due to dissemination from an extracranial tuberculous foci, most often the lungs (31). Based on the negative T-SPOT blood test, blood/CSF bacteria culture, CSF genomic sequencing of common microorganisms, we could exclude TB as the diagnosis.

The radiology department report also suggested parasites (e.g., cysticercosis) as a possible diagnosis. Cysticercosis occurs when an individual ingests the eggs of the tapeworm Taenia solium. This often occurs when the person ingest food contaminated with feces from a Taenia solium tapeworm carrier, the person then become an intermediate secondary host for the parasite. The larvae spread by hematogenous dissemination to several parts of the body such as the skeletal muscles, subcutaneous tissues, ocular tissues and central nervous system (CNS). Neurocysticercosis occurs when the larvae infiltrates the brain parenchyma. Parenchymal cysticercosis natural lifecycle is divided into four stages: vesicular, colloidal vesicular, granular nodular and nodular calcified stage (32). On the first MRI set of our patient, a nodular lesion with a central dot can be seen in the left parietal lobe on T2 and ADC. This lesion can superficially resemble a cysticerci with a central scolex. Cysticerci in the colloidal vesicular and granular nodular stage also shows surrounding edema (32). The main difference is, on T2 imaging, cysticerci lesions are highly hyperintense (32). This contrast to our patient’s lesion being isointense on T2. Cysticerci lesions also only shows rim enhancement on T1 post contrast (32) whereas our patients’s lesion were homogeneously enhancing post contrast. We excluded cysticercosis by CSF genomic sequencing of common microorganisms and serum analysis for Cysticercus IgG, both tests came up negative.

The lesion with the central dot seen on T2 and ADC in the left parietal lobe can also be mistaken for cerebral Toxoplasmosis. Toxoplasmosis is a protozoan infection that predominantly affect immunocompromise patients. Cerebral toxoplasmosis often present as multiple (usually) or singular lesions, the lesions often show a target sign and are hypointense on T2 with a hyperintense dot like core (32), which can superficially resemble our patient’s left parietal lobe lesion. Toxoplasmosis lesions also show restricted diffusion on ADC (32), a characteristic also shared by our patient’s lesion. The difference lies on T1 after contrast administration, toxoplasmosis lesions show rim like enhancement (32) whereas our patient’s lesions show homogenous enhancement. Toxoplasmosis lesion with target sign are also usually more hypointense on T2 than our patient’s lesion. Cerebral toxoplasmosis usually affects severely immunocompromised individuals such as HIV infected patients in the terminal acquired immunodeficiency syndrome (AIDS) stage or organ transplant recipients. Patients’ laboratory test and history did not reveal any condition that may cause immune deficit and so in our case, we did not consider this as a differential diagnosis.

Cerebral Schistosomiasis was also considered among our differential diagnosis. Schistosomiasis is caused by trematode blood flukes of the genus Schistosoma. Three species of Schistosomes commonly affect humans: Schistosoma japonicum, Schistosoma hematobium and Schistosoma mansoni (33). These three species of Schistosomal worms all requires a different species of freshwater snail as their intermediate secondary host (33). The geographical distribution of the Schistosomal fluke species is dependent on the geographical distribution of their respective host snail species. Schistosoma japonicum is the only Schistosomal worm species native to China, it is present in eastern and southern China. Its distribution includes the middle and lower portion of the Yangze river drainage which passes through Nanjing, the city where our patient reside. When there is CNS involvement, Schistosoma japonicum typically affect the brain (33) whereas the other two species generally affect the spinal cord. On contrast enhanced MRI, Schistosoma japonicum lesions typically appears as multiple intensely enhancing nodules clustered together (33). Sometimes an area of linear enhancement can be seen, the lesions are also surrounded by an area of edema. Our patient’s lesions may also appear superficially similar on post contrast T1 images but Schistosoma japonicum nodules tend to be much more closely clustered together when compared to our patient’s nodular lesions. We excluded schistosomiasis based on the negative results in stool microscopy for parasite eggs, CSF genomic sequencing of common parasites and serum analysis for Schistosoma IgG. Key similarities and differences on MRI imaging between our patient’s lesions and standard lesions of the most common forms of TB, Neurocysticercosis, Toxoplasmosis and Schistosomiasis most likely to be confused with delayed NICE lesions can be found in Table 5.

We also highly suspected cerebral parasitic infection due to the elevated blood eosinophil count of our patient but we very thoroughly screened blood, CSF and stool for most possible infectious differential diagnosis, no positive results were found. The detailed test and results can be found in Tables 2,3.

One of the possible non infectious differential diagnosis of NICE lesions is DPHL. This condition is characterised clinically by neurologic deterioration and changes on imaging usually manifesting after one to four weeks following a prolonged episode of cerebral anoxia (34,35). it has been reported following cases of respiratory failure due to drug overdose, usually opiods, benzodiazepine or barbiturates, anemic anoxia due to carbon monoxide poisoning, ischemic anoxia due to cardiac arrest following cardiopulmoany embolism (34) or surgical anesthesia complications. It has also been reported after cases of strangulation (35). This condition has a characteristic lucid interval where the patient recovers (fully or partially) from the initial anoxic event only to suffer from a neurological relapse a few weeks after the event. The typical clinical manifestation are neuropsychiatric symptoms such as bizarre erratic behaviour, delusions, ataxia, akinetic mutism and urinary/fecal incontinence (34). The typical characteristics of this disorder on imaging has been described as bilateral symmetrical lesions seen in the white matter especially at the centrum semioval and periventricularly (34). The lesions are hyperintense on T2 and FLAIR sequence with increased signal intensity on DWI and hypointense on ADC mapping, no contrast enhancement is seen on gadolinium administration (34). One of the suspected pathophysiology of DPHL is demyelination due to anoxic injury to myelin producing enzymatic systems (35).

DPHL can also be confused with delayed NICE lesions as in the literature, several authors (9,11,13,15,17,24) has referred to NICE lesions as delayed leucoencepalopathy. while both DPHL and delayed NICE lesions occurs after a delayed period after the initial precipitating event (endovascular therapy for NICE lesions and anoxic episodes for DPHL), delayed NICE lesions can occur following endovascular treatment without any anoxic episodes, such as aneurysm coiling and diagnostic DSA. Delayed NICE lesions most often manifest clinically as focal motor deficit such as hemiparesis, or aphasia (11) which differs from the neuropsychiatric behaviour (delusion, erratic behaviour, disinhibition) (34) seen in DPHL. On imaging, both DPHL and delayed NICE lesions shows areas of high signal intensity on T2 and FLAIR restricted to the white matter region but in cases of delayed NICE lesions, the pathological area is mostly restricted to the vessel that received endovascular treatment. The lesions are usually bilateral and symmetrical in DPHL cases. DPHL lesions also shows high intensity areas on DWI sequence whereas in cases of delayed NICE lesions where no ischemia occurred such as aneurysm coiling, no high signal changes are seen on DWI (9). DPHL lesions do not enhance after contrast administration compare to the highly contrast enhancing delayed NICE lesions. It is important to differentiate DPHL from NICE lesions as NICE lesions respond favorably to medical treatment whereas no treatment apart from supportive management is currently available for DPHL (34).

In our case, as our patient did not experience any period of cerebral anoxia, we did not consider it as possible differential diagnosis.

Diagnostic workup

Delayed NICE lesions following endovascular treatment is a diagnosis of exclusion, we first had to eliminate the possibility of all possible differentials in order to make the diagnosis

We sent blood, CSF, and stool for laboratory test. Blood test sent were: routine blood chemistry, full blood count, coagulation profile, inflammatory markers levels, infectious diseases test, test for autoimmune systemic diseases such as SLE (systemic lupus erythematosus), autoimmune vasculitis and autoimmune encephalitis.

CSF was sent for biochemistry test, cell count, bacterial culture and analysis for any pathogenic organisms. Stool was tested for parasites and fungus.

The details and results of all relevant laboratory test done before and after administering steroid treatment can be found in Table 2,3. We also present the noticeable changes found on laboratory test before and after steroids in Table 4.

As we did not find any evidence of any infectious or autoimmune diseases, we made the final diagnosis of “Delayed NICE lesions following neuroendovascular intervention”.

To be noted that we first started treatment with antibiotics and then proceeded with steroids before getting the results of all laboratory tests as we did not want to delay treatment.

There is currently no standard guideline for the diagnostic workup of delayed NICE lesions, we suggest that for any patient presenting with lesions on MRI (symptomatic or asymptomatic) typical of delayed NICE lesions, 4 days and up to 4 years after any neuroendovascular procedure:

• Send blood, CSF and stool for laboratory test.
• Starting broad spectrum antibiotic treatment while waiting for results of tests for pathogenic bacteria, fungi and parasites.
• Stopping antibiotics and starting steroid after having ruled out any infectious differentials.
• Continue steroid therapy while waiting for results of tests for autoimmune disorders.
• Continue steroid treatment if autoimmune disorders are ruled out.

Treatment options

As delayed NICE lesions are a relatively rare condition, there is currently no standard treatment protocol in place. Previously described cases were all treated according to the discretion of the treating clinician. The vast majority of cases were treated using steroid pulse therapy, Patients were first given high dose steroid by intravenous (IV) or oral route, followed by tapering down of the dosage over period of months to years. Not all reviewed articles provided the dosage and duration of treatment in details. A few examples of steroid regimen prescribed were: IV methylprednisolone 1,000 mg/day for 3 days followed by oral prednisolone of 20 mg/day, slowly tapering the dosage for up to 4 months (7). Single loading dose of 40 mg IV dexamethasone followed by 8 mg oral dexamethasone 3 times daily for 10 days, tapering to 2 mg three times daily for 3 months (11). Oral methylprednisolone 96 mg daily tapered slowly over 2 months (17), 100 mg oral prednisolone tapered over 5 months (17).

Ikemura et al. (9) reported 9 asymptomatic cases that were not given any treatment but only observation. The same author reported one case treated with free radical scavengers in addition to steroid but did not mention the specific drug and dosage.

There are also reported cases describing symptomatic patients recovering with disappearance of lesions on MRI without any medical treatment (27,36).

Several authors reported the relapse of the condition following tapering off and discontinuing steroid (10,14,15,17,20,24). Very few articles mention the use of agents other than glucocorticoids. A case series (17) reported the addition of oral cyclophosphamide (100 mg daily switched to IV 10 mg/kg due to lymphopenia) to glucocorticoid treatment. Cyclophosphamide was added to the concerned patient treatment due to severe relapse of symptoms and lesions on imaging following discontinuation of glucosteroid. Lorentzen et al. (14) reported the use of azathioprine (2 mg/kg daily) in addition to prednisolone, also following relapse after steroid discontinuation. Grewal et al. (20) reported the use of mycophenolate (dosage not mentioned) in addition to steroid, also due to relapse after tapering off steroids. Bayas et al. (10) described 5 patients treated with other immunosuppressants in addition to steroids. They described the use of azathioprine (125–150 mg daily), cyclophosphamide, mycophenolate mofetil (2 mg daily), methotrexate (7.5 mg weekly), rituximad and tocilizumad. They first started with the use of less selective immunosuppressing agents, reserving monoclonal antibodies only for treatment resistant cases. They found a positive response to treatment only with glucocorticoid, tocilizumad and mycophenolate mofetil.

Our treatment suggestion plan is: for confirmed delayed NICE lesions cases (lesions showing delayed NICE characteristics on MRI, occurring 4 days to 4 years following endovascular procedure, after excluding all differential diagnosis), if the patient is asymptomatic, only regular follow up is required. With symptomatic patients, the use of steroid pulse therapy and MRI exam follow up of lesions at regular interval is warranted. We suggest the use of IV methylprednisolone 120 mg daily for 5 days, followed by daily 60 mg oral prednisolone, tapering down according to patient response to treatment, both on imaging and physical examination. If patient relapse during lowering of steroid dosage or discontinuing steroids, other immunosuppressing drugs can be used in addition to steroid treatment. It should be noted that our patient first received IV dexamethasone 10 mg daily for two days when she was first admitted under the provisional diagnosis of acute ischemic stroke. She was put on a relatively low dose of steroid for only two days and the medication was then stopped. No improvement was seen in her condition. We only saw a positive response three days after we started IV methylprednisolone 120 mg daily.

Conclusions

Delayed NICE lesions is still a very rare complication of endovascular treatment. More cases are expected to emerge as neuroendovascular procedures are starting to be perform in more hospitals worldwide. It is important for clinicians to be able to recognize and consider delayed NICE lesions as a differential diagnosis if characteristic lesions are found on MRI after endovascular procedure. Clinicians should be familiar with its differential workup and available treatment. This will reduce morbidity and length of hospitalization. As delayed NICE lesions may become a chronic condition where patients need to be maintained on long term immunosuppressants due to relapse, clinicians should be familiar with the different drugs, combinations and dosage most likely to result in remission. We suggest that for patients undergoing elective endovascular procedures, hospitals can propose to patients relatively simple and inexpensive tests, such as skin allergy test for metals such as nickel, platinium, titanium and also PGLA from commonly used stents and coils. Materials use for surgery can then be more properly selected to maybe reduce the incidence of this complication. More clinical researches need to be done regarding the risk factors of delayed NICE lesions such as types of endovascular materials use, type of procedures and characteristics of procedure with respect to its incidence. This may allow neurointerventionist to tailor procedures in a way as to decrease the risk of this complication. We also think that more case reports should be publish describing in detail the treatment regiment utilized and patient response as the information are currently scarce in the literature.

Acknowledgments

None.

Footnote

Funding: The study was supported by the National Natural Science Foundation of China (No. 82101497 to T.G.), Natural Science Foundation of Jiangsu Province (No. BK20210967 to T.G.), and Jiangsu research hospital association for neurointervention (No. JY202303 to Z.W.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-395/coif). T.G. reports that the article was funded by the National Natural Science Foundation of China (No. 82101497) and Natural Science Foundation of Jiangsu Province (No. BK20210967). Z.W. reports that the article was funded by Jiangsu Research Hospital Association for Neurointervention (No. JY202303). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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