Effectiveness of Infliximab for Refractory Non-ischemic Cerebral Enhancing Foreign-body Granulomatous Lesions Following Endovascular Therapy

Abstract

Objectives:

Non-ischemic cerebral enhancing (NICE) foreign-body granulomatous lesions are an immune-mediated complication of endovascular therapy (EVT). No single immunotherapy has demonstrated consistent effectiveness. We highlight the novel use of tumor necrosis factor (TNF)-α inhibition in treating refractory NICE lesions.

Methods:

This multi-center case series describes three patients with refractory NICE lesions (recurrent seizures, persistent MRI enhancement, and/or steroid dependence with failure of ≥ 1 maintenance immunotherapy) treated with infliximab. Their clinical course, evaluation, and outcomes are detailed.

Results:

Patients were female (median age 57 years [range 56–58]), presenting with headache and seizures within six months of EVT for intracranial aneurysm (n=2) or carotid stenosis (n=1). MRI (n=3) revealed unilateral nodular enhancement with vasogenic edema, and brain biopsy (n=2) revealed foreign-body granulomatous inflammation. All patients developed refractory disease and steroid dependence despite ≥1 immunotherapy including mycophenolate (n=3), rituximab (n=1), and/or cyclophosphamide (n=1). Infliximab treatment resulted in significant clinical and radiological improvement in all three patients.

Discussion:

TNF-α inhibition may be an effective targeted treatment strategy for NICE foreign-body granulomatous lesions, expanding treatment options for patients with refractory disease. Larger prospective studies are needed to establish treatment guidelines aimed at improving outcomes in individuals with refractory disease.

Classification of Evidence:

This article provides Class IV evidence that infliximab may have potential benefit in patients with non-ischemic cerebral enhancing (NICE) lesions following endovascular therapy (EVT).

Introduction:

Non-ischemic cerebral enhancing (NICE) lesions are a foreign-body reaction to polymer micro-emboli following endovascular therapy (EVT; aneurysm repair, thrombectomy, revascularization).^1,2 Headache, seizure, motor and visual deficits can occur, with brain MRI demonstrating nodular enhancement and perilesional edema in associated vascular territories.¹

While often self-limited (median lesion resolution of 13 weeks [IQR 6–30]), refractory disease can occur, with no single treatment demonstrating consistent efficacy.^1,3,4 This multi-center case series describes three women (median age 57 years [range 56–58]) with refractory (ongoing clinical-radiological activity despite ≥ 1 maintenance immunotherapy) NICE lesions that improved with infliximab. We detail their clinical course, highlighting infliximab as a potentially effective therapy for this debilitating condition.

This study’s primary research question explores whether TNF- α inhibition is an effective treatment in individuals with refractory NICE lesions, defined as recurrent seizures, persistent MRI enhancement, and/or steroid dependence with failure of ≥ 1 maintenance immunotherapy.

Methods

Standard Protocol Approvals, Registrations, and Consent

This study was approved by the Mayo Clinic Institutional Review Board. Consent was obtained from all patients or legally authorized representatives.

Data Availability

Anonymized data not published within this article is available by request from qualified investigators.

Case 1

A 57-year-old woman developed transient right hemiparesis, hemianesthesia, and dysarthria. Brain MRI was unrevealing, consistent with a TIA. CT angiogram revealed left internal carotid artery (ICA) stenosis, treated with angioplasty and stenting. Three months later she developed episodic expressive aphasia, right face and arm clonus, and headache. Brain MRI revealed enhancing left hemispheric T2 hyperintensities(Figure 1;1A,1B). CSF was pleocytotic (WBC 6/µL;78% lymphocytes). EEG revealed left frontocentral slowing without epileptogenicity. Levetiracetam was increased, with addition of carbamazepine and valproate due to ongoing right face and arm clonus.

Figure 1. Radiographic Features of Non-ischemic Cerebral Enhancing Lesions Before and After Infliximab therapy.

Initial MRI (column 1 and 2) prior to treatment initiation with T1 post-gadolinium (A) nodular enhancement and (B) T2/FLAIR vasogenic edema representing patient 1 (1A, B), patient 2 (2A, B), and patient 3 (3A, B). Follow-up MRI (column 3 and 4) after treatment with cyclophosphamide (1C, 1D), rituximab (2C, 2D), and mycophenolate (3C, 3D). Final MRI (column 5 and 6) following initiation of infliximab at 4 years (patient 1; 1E, 1F), at 3 months (patient 2; 2E, 2F), and at 6 months (patient 3; 3E, 3F).

At two months, MRI demonstrated persistent enhancement. Frontal lobe biopsy revealed foreign-body granulomatous inflammation with multinucleated giant cells. She initiated IV methylprednisolone (IVMP), mycophenolate 2g, and a prednisone taper (see eFigure 1 for treatment timeline). Headaches and seizures improved, but recurred below 10mg prednisone, with increased left hemispheric nodular enhancement on MRI. Despite six months of mycophenolate, MRI showed persistent enhancement. She transitioned to IV cyclophosphamide 1g/m² monthly for six months but continued to experience focal motor seizures progressing to Epilepsia Partialis Continua with continued radiologic activity(Figure 1;1C, 1D).

Approximately 30 months from presentation, refractory disease despite second-line immunotherapy and histopathological evidence of granulomatous disease, prompted initiation of a targeted treatment with tumor necrosis factor (TNF)-α inhibition. She initiated infliximab 5mg/kg monthly and eight-week IVMP. After six months, her seizures abated, and her MRI improved, with two residual areas of enhancement. Infliximab was increased to 8mg/kg monthly and her nine-month MRI showed complete resolution. She discontinued steroids and valproic acid. Two years following infliximab initiation, loss of insurance coverage led to infliximab discontinuation. She developed recurrent radiologic enhancing lesions, improving with infliximab re-initiation. Four years after initiating infliximab, she remains seizure free on two anti-seizure medications, off steroids, and free of left cerebral hemispheric enhancement(Figure 1;1E,1F).

Case 2

A 56-year-old woman underwent coil embolization of a right middle cerebral artery aneurysm. Four months later she developed left hemiparesis, homonymous hemianopsia, and focal motor seizures, necessitating levetiracetam. Brain MRI revealed enhancing right hemispheric T2 hyperintensities(Figure 1;2A,2B). CSF was non-inflammatory. Whole-body PET demonstrated a solitary lung nodule, with biopsy revealing non-small cell lung cancer treated with radiotherapy.

Prednisone 60mg tapered over three months provided temporary symptom control. Dose reductions below 20mg resulted in recurrent left hemiparesis, seizures, and radiographic progression. Mycophenolate initiated 20 months post-intervention up to 2g daily yielded no appreciable clinical or radiographic response. Rituximab 1000mg every six months resulted in temporary improvement with eventual radiographic recurrence(Figure 1;2C,2D). Mycophenolate was reintroduced at 3g daily. Right parietal biopsy 40 months post-intervention revealed focal granulomas and multinucleated foreign-body giant cells(Figure 2) consistent with NICE lesions.

Figure 2. Histopathology of NICE lesions.

Representative histopathology from patient 2 with (A-B) granulomatous inflammation without necrosis (H&E, 20x). (C-D) A non-polarizable filamentous structure (yellow arrow) is observed in proximity to multinucleated/foreign-body giant cells (white arrow), with no acid-fast or fungal organisms present on special stains (C: Fite; D: PAS, 10x). (E) CD68 immunohistochemistry highlights macrophages/histiocytes and multinucleated giant cells associated with the filamentous structure (10x). (F) An occluded blood vessel is seen in relation to the non-polarizable filamentous structure (VVG, elastin stain, 10x).

Following a patient-centered shared decision-making process discussing the potential risks and benefits of TNF-α inhibition, rituximab was discontinued, and infliximab initiated at 47 months alongside mycophenolate 3g daily. A substantial reduction of radiographic enhancement and seizures occurred within three months(Figure 1;2E,2F). Mycophenolate was reduced to 1g daily. Shortly after starting infliximab, new left temporal lobe and thalamic lesions were biopsied confirming metastatic adenocarcinoma. Brain metastases were treated with stereotactic radiosurgery; chemotherapy was deferred due to poor performance status. Infliximab was held for 17 weeks with clinical-radiological stability, then resumed at 5mg/kg every 12 weeks. She has since developed malignant pleural effusions, and hospice discussions are ongoing.

Case 3

A 58-year-old woman developed severe headache two days after coiling of a left ICA aneurysm, evolving to recurrent headaches, transient visual disturbance, and a generalized tonic-clonic seizure over three weeks. Brain MRI revealed left cerebral hemispheric T2 hyperintensities and multifocal enhancement(Figure 1;3A,3B). Levetiracetam and prednisone 20mg were initiated. Repeat MRI brain one month later showed a reduction in enhancement and vasogenic edema. Decreasing prednisone below 10mg led to recurrent visual disturbance and worsening headaches. CSF evaluation was non-inflammatory. Her diagnosis was consistent with NICE lesions. Prednisone was increased to 60mg with a taper and mycophenolate 2g was added.

Despite mycophenolate, prednisone taper led to recurrent cerebral edema and enhancement(Figure 1;3C,3D). She was initiated on infliximab 5 mg/kg every four weeks. After six months of infliximab treatment, brain MRI revealed complete resolution of her enhancing lesions(Figure 1; 3E, 3F) She remains on prednisone 5 mg, tapering by 1 mg monthly.

Classification of Evidence:

This article provides Class IV evidence that infliximab may have potential benefit in patients with non-ischemic cerebral enhancing (NICE) lesions following endovascular therapy (EVT).

Discussion

We describe the novel use of TNF-α inhibition as a potential treatment for NICE lesions. Patients were women in their late 50’s with refractory disease (recurrent seizures, persistent MRI enhancement, steroid dependence) and failure of ≥ 1 immunotherapy: mycophenolate (n=3), rituximab (n=1), cyclophosphamide (n=1;Table 1). Clinical-radiological improvement occurred within three months of initiating infliximab, with steroid independence and a marked reduction in MRI enhancement. Patient 1 experienced resolution of her refractory seizures following infliximab, and recurrence after discontinuation, underscoring the effectiveness of infliximab and the risk of relapse.

Table 1.

Clinical characteristics in three cases of refractory non-ischemic cerebral enhancing (NICE) lesions treated with infliximab

	Case 1	Case 2	Case 3
Age	57	56	58
Procedure	Left ICA stenosis angioplasty and stenting	Right proximal MCA aneurysm coil embolization and stenting	Left ICA aneurysm coil embolization and stenting
Procedure to Symptom Onset	3 months	4 months	2 days
Presenting Symptoms	Seizures - expressive aphasia & right facial twitching	Left hemiparesis & focal motor seizures	Recurrent headaches, visual disturbance, seizures
Seizures	Yes	Yes	Yes
Headache	Yes	Yes	Yes
Initial Brain MRI Findings	Left hemispheric vasogenic edema with punctate and linear enhancement	Right hemispheric vasogenic edema with nodular enhancement and microhemorrhage	Left hemispheric vasogenic edema with nodular enhancement and microhemorrhage
EEG Findings	Left central spikes and sharp wave discharges	Right hemisphere slowing; no interictal epileptiform discharges	Normal
CSF WBC	6/µL	1/µL	1/µL
CSF Protein	78 mg/dL	25 mg/dL	37 mg/dL
Pathology	Foreign body-type granulomatous inflammation with foreign-body & multinucleated giant cells & reactive change	Foreign body-type granulomatous inflammation with foreign body & multinucleated giant cells, and non-polarizable filamentous structures	Not Performed
Number ASM required	3	1	1
ASM dosing	LEV 3g, CBZ 400mg, VPA 2.5g	LEV 1.5g	LEV 1.5g
Steroid Dependent	Yes	Yes	Yes
Steroid Requirement	10 mg	20 mg	10 mg
Symptom onset to Initial Immunotherapy	1.5 months	3 months	2 months
Maximum Immunotherapies Failed	MMF 2g x 6 months Cyc 1 g/m x 6 months	MMF 3g x 21 months RTX 1g every 6 months x 22 months (4 cycles)	MMF 2g x 12 months
Symptom onset to Infliximab	30 months	42 months	21 months
Infliximab Dose	8 mg/kg every 4 weeks	5 mg/kg every 8–12 weeks	5 mg/kg every 4 weeks
Weaned off steroids following Infliximab	Yes	Yes	Successfully weaning, currently on 5 mg
Clinical Response following Infliximab	Seizure free on two ASM, recurrent headaches	Frequency of focal motor seizures greatly improved	Seizure free on one ASM
Radiological Response following Infliximab	Complete resolution of left cerebral enhancement at nine months	Marked improvement of right cerebral enhancement at three months; dose increase was not pursued due to brain metastasis identified on follow up scan	Complete resolution of left cerebral enhancement at six months

ASM = Anti-Seizure Medicine; CBZ= Carbamazepine; Cyc = Cyclophosphamide; EEG = Electroencephalogram; CSF = Cerebrospinal Fluid; ICA= Internal Carotid Artery; LEV=Levetiracetam; MCA = Middle Cerebral Artery; MMF = Mycophenolate; MRI = Magnetic Resonance Imaging; RTX = Rituximab; VPA= Valproic Acid

NICE lesions occur in 0.05%−2.3% of patients following EVT, ^1,5 predominantly affecting women.^4,5,6,7 Clinical course is variable, involving asymptomatic disease, self-limited disease requiring minimal or no treatment, or refractory disease.^4,6 A type IV granulomatous hypersensitivity reaction to a non-biodegradable polymer released from endovascular catheters is evident across multiple organs, with histopathology mimicking sarcoidosis. ^7,8,9,10,11 TNF-α is a key cytokine involved in granuloma formation via macrophage recruitment, providing rationale for infliximab as a potentially effective treatment for NICE lesions.¹²

Currently, no immunotherapy shows consistent effectiveness for treating NICE lesions.³ Rituximab and cyclophosphamide may be effective,⁴ although our patients failed both. The use of TNF-α inhibitors for refractory NICE lesions is not previously reported in the literature. In this series, all patients achieved a radiographic response within three months of initiating infliximab, with patient 1 remaining stable over four years on treatment, except after therapy discontinuation.

NICE lesions likely remain underrecognized and underdiagnosed, partly due to their variable description in the literature.² As indications for EVT grow, the incidence of NICE lesions will likely increase. ¹³ It is critical this entity be recognized and treated effectively to prevent neurological morbidity.

Importantly, the use of TNF-α inhibitors carries risk, including inflammatory CNS events and infection.¹⁴ Additionally, infliximab’s FDA label warns of a potential malignancy association, although the absolute risk is considered low as supported by observational studies.¹⁵ Clinical trials comparing TNF-α inhibitors to other immunotherapies in granulomatous disease are lacking, and their effectiveness as a monotherapy is not yet well established.¹¹ We acknowledge the possibility that prolonged prior treatment with alternative immunotherapies may have contributed to the clinical improvement demonstrated with infliximab. Future efforts should establish effective therapeutic options for refractory NICE lesions on a larger scale to optimize outcomes for this debilitating yet treatable condition.

Full Data Access and Statements

The principal author has full access to the data used in this manuscript and takes full responsibility for the data, the analyses and interpretation, and the conduct of the research, and has the right to publish all data, separate and apart from the guidance of any sponsor.