Introduction
The pathophysiology of NR is complex and is not fully understood.1, 2, 3 It involves much more than just distal embolization of thrombotic debris. Indeed, many phenomena contribute to NR: leukocyte infiltration, vasoconstriction, activation of inflammatory pathways and cellular edema.4, 5 Recently, experimental data demonstrated the important roles played by vascular damage and haemorrhage in the establishment of NR. Vascular permeability at the endothelial level appears to be a major factor in NR.6, 7 It starts with endothelial injury by endovascular hardwares.
A major regulator of endothelial integrity is vascular endothelial growth factor (VEGF), which was originally called vascular permeability factor. VEGF is expressed in response to endothelial injury. In a resting state, VEGF receptor 2 forms a complex with vascular endothelial (VE)-cadherin,8, 9 an endothelial-specific adhesion protein that stabilizes intercellular adherence junctions. Injury-induced VEGF, when binding to VEGF receptor 2, dissociates the VEGF receptor 2/VE-cadherin complex, leading to an increase in endothelial permeability. VEGF activates Src phosphorylation, which then induces tyrosine phosphorylation of VE-cadherin and its internalization; this reduces the amount of VE-cadherin available at interendothelial junctions, thus leading to disruption of endothelial barrier integrity. In vivo, VE-cadherin phosphorylation is also modulated by the haemodynamic forces and shear stress to which endothelial cells are exposed. So, driven by its phosphorylation state, VE-cadherin plays a major role in maintaining strong interendothelial junctions. In experimental models, vascular permeability plays a central role in NR. However there are few data from human patients on the basal phosphorylation levels of VE-cadherin, which might represent a new angle for preventing or treating NR. Endothelial hypersensitivity is another factor.
One other factor is ruptured plaque with thrombus and atherosclerotic material leading to distal embolization of microthrombi and plaque components. This distal embolization is also involved in the NR phenomenon. 10
The term NR came naturally after the observation of the absence of flow despite correct stents and/or coils placement or sometime only after angiography and catheter manipulation.
NR can be quantified in angiography by TICI classification (TICI 1-no/minimal reperfusion, 2a-partial filling less than 50% territory, 2b-partial filling more than 50% territory, TICI 2c-near complete perfusion except slow flow or few distal cortical emboli, tici 3-complete perfusion)
Materials and Methods
This was an open single center prospective case– control study. Neurosurgery department of Dr. R.M.L.I.M.S. have biplane cath lab of Toshiba. Here we provide all kind of endovascular neurosurgery facility. From march 2017 to march 2021, we prospectively analysed 153 patients who underwent major neuro-endovascular procedures. 81 patients were female and 72 patients were male.142 patients presented with subarachnoid haemorrhage of varying grade after ruptured intracranial aneurysm. In these 142 patients recieved coiling with or without stent/flow diverter was done. Rest 11 patients presented with unrupured giant intracranial aneurysm. In these unruptured giant aneurysm, flow diverter/intrasaccular device was placed. The overall outcome of the patients was dependent upon pre-procedural neurological grade and presence or absence of intra-procedural complications mainly.
NR phenomenon was defined as: Angiographic evidence of no flow of dye in small to large segmental portion of large and medium sized artery or arteries despite no evidence of dissection, spasm, stenosis or thrombus. Earlier the flow of dye was present without delay before quick development of this phenomenon.
The main inclusion criteria were patients with ruptured or unruptured aneurysms undergoing endovascular procedure in neurosurgery cath lab between march 2017-march 2021.
Clinical outcomes immediate post-procedure and at discharge were recorded. Angiographic findings were noted at the onset of NR and after management of NR.
Pre-procedure GCS and other neurological status were compared with post-procedure GCS and other neurological status.
Figure 1
A): demonstrate medium size MCA aneurysm, next image; B): shows aneurysm tightly packed with coils. Further images; C-F): depict serial development of no flow/ no reflow, immediately after coiling procedure, meanwhile pharmacological measures were taken to abolish NR phenomenon. And finally; G): in the last image we were successful in restoring the flow in both MCA and ACA. Post-intervention the patient developed right hemiparesis which was gradually resolving with conservative management.
Results
The study enrolled 153 patients (72 male, 81 female) with a mean age of 56 years (range 34–78 years). NR phenomenon was reported in 11 cases (7.2%) and occurred during catheter and wire navigation, during coiling stenting or immediately post-coil/stent placement
Following stent/flow diverter 6 (54.54%), after stent/flow diverter with coil 3(27.27%) and after coil placement 2(18.18%).
The clinical characteristics of those developing NR were explored compared with the control group (those who did not develop NR).
The former group was an older population with increased medical history of hypertension and presented with higher systolic blood pressures. Patients with NR had a delay across all recorded timings related to symptom onset and clinical interventions, when compared with the patients who did not. NR group included patients with obesity, DM, arteritis, multiorgan and multicentric arteriopathy, dyslipidemia, autoimmune diseases.
Analysis of the angiographical images demonstrated that the culprit vessel/vessels including parent vessel was abnormal angiographically with irregularity and stenosis. Difficult access, hardware reuse, complex pathology requiring more than simple coiling, requirement of multiple maneuvers and time taking procedures were all related with occurrence of NR.
Baseline flow was not reduced but post-procedure flow was significantly reduced, often absent (TICI 1 or 2a)
Patients in NR group had longer time to access the pathology with more efforts and unusual methods. More hardware’s were used in NR group. More metal in the form of multiple coils balloons and larger stents were used in NR group
Patients with NR had increased risk of in-hospital death and disability (1 patient/9.1% death, 8 patients/72.72% with one or multiple neurological dysfunction with varying severity) in comparison to patients without NR(4 patients/2.8% deaths and 12 patients/8.5% disabilities, out of 142 patients).
Discussion
NR is a segmental phenomenon rather than focal. It have patient related risk factors as well as procedure related risk factors. Thus identifying high risk patient and adapting different interventional strategy may alter the outcome. Though large number multicentric trial is needed to draw a statistical conclusion. A lot of cardiology literature is available about no-reflow phenomenon but not in neuro-endovascular literature. This phenomenon have peculiar presentation and specific management strategy. Awareness among neuro-endovascular surgeons is necessary. If the intra-procedural NR is left unmanaged, the outcome is not favourable often. So sensitization towards recognizing NR and immediate management is necessary. High risk group identification is also necessary. By recognizing high risk group of patients and procedures, we can do pre-conditioning, post-conditioning and adaptation of safer interventional strategy. Also further research is needed for the management strategy of NR. Current main stay of management are beta blockers (metoprolol), vasodilators (nimodipine, sod. nitroprusside, nicorandil, nicardipine, verapamil), adenosine, Gp 2b/3a inhibitor, P2Y12 inhibitors and cyclosporine A. In authors’ experience steroid is also beneficial.
NR is not a problem of canalization but it is a problem of flow. Dye don’t flow across the segment in question and hence the blood but wires and catheters can be passed in the segment although it is not advisable and it is better to abandon the procedure after managing NR in authors’ opinion.
NR starts with endothelial damage by mechanical shearing, hypersensitivity or ischaemia. After this there is endothelial swelling, neutrophil and platelet aggregation, vasospasm, and endothelial leakage. The cut-off margin during angiography in NR is abrupt and sharp with no filling defect and abnormality in margin. There are literature and evidences that endothelial hypersensitivity and inflammatory cascade spread through tight endothelial junctions to neighboring areas and the phenomenon becomes segmental.
There is scope of future research in the form of causative and risk factor validation, NR in neuro-endovascular surgery, exact pathophysiology of NR and pharmacological treatment.
Conclusion
NR is a rare but unfavorable complication during neuro-endovascular surgery. Difficult access to pathology manipulation and maneuvering and heavy implantation in the form of coils and stents as well as patient factors appear responsible for its causation. Although multicenter large number studies and further research is required.
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