Peri-Lead Edema in Deep Brain Stimulation: Long-Term Outcomes and Possible Etiological Correlates

Peri-Lead Edema in Deep Brain Stimulation: Long-Term Outcomes and Possible Etiological Correlates | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Peri-Lead Edema in Deep Brain Stimulation: Long-Term Outcomes and Possible Etiological Correlates View ORCID Profile Luigi G. Remore , Giorgio Fiore , Elena Pirola , Linda Borellini , Francesca Mameli , Fabiana Ruggiero , Eleonora Zirone , Roberta Ferrucci , Filippo Cogiamanian , Enrico Mailland , Antonella M. Ampollini , Giulio A. Bertani , Stefania E. Navone , Giovanni Marfia , Ioannis U. Isaias , Marco Locatelli doi: https://doi.org/10.1101/2025.05.01.25326737 Luigi G. Remore 1 Neurosurgery Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico , Milan, Italy 2 Department of Pathophysiology and Transplantation, University of Milan , Milan, Italy MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Luigi G. Remore For correspondence: luigigianmaria.remore{at}gmail.com Giorgio Fiore 1 Neurosurgery Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico , Milan, Italy MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Elena Pirola 1 Neurosurgery Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico , Milan, Italy MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Linda Borellini 3 Neuropathophysiology Unit, Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico , Milan, Italy MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Francesca Mameli 3 Neuropathophysiology Unit, Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico , Milan, Italy PsyD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Fabiana Ruggiero 3 Neuropathophysiology Unit, Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico , Milan, Italy PsyD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Eleonora Zirone 3 Neuropathophysiology Unit, Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico , Milan, Italy PsyD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Roberta Ferrucci 3 Neuropathophysiology Unit, Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico , Milan, Italy PsyD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Filippo Cogiamanian 3 Neuropathophysiology Unit, Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico , Milan, Italy MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Enrico Mailland 3 Neuropathophysiology Unit, Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico , Milan, Italy MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Antonella M. Ampollini 1 Neurosurgery Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico , Milan, Italy MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Giulio A. Bertani 1 Neurosurgery Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico , Milan, Italy MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Stefania E. Navone 1 Neurosurgery Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico , Milan, Italy 4 Laboratory of Experimental Neurosurgery and Cell Therapy, Unit of Neurosurgery, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico , Milan, Italy PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Giovanni Marfia 1 Neurosurgery Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico , Milan, Italy 4 Laboratory of Experimental Neurosurgery and Cell Therapy, Unit of Neurosurgery, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico , Milan, Italy MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ioannis U. Isaias 5 Parkinson Institute of Milan, ASST G. Pini-CTO , Milan, Italy 6 University Hospital of Wuerzburg and Julius Maximilian University of Wuerzburg , Wuerzburg, Germany MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Marco Locatelli 1 Neurosurgery Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico , Milan, Italy 2 Department of Pathophysiology and Transplantation, University of Milan , Milan, Italy MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF Abstract Background Deep brain stimulation (DBS) is an effective surgical procedure for the treatment of Parkinson’s disease (PD) and other movement disorders. Immediate and delayed complications after DBS surgery have been described. Peri-lead edema (PLE) is a DBS-related complication whose etiology is still unknown. Moreover, PLE frequency and long-term effects are subjects of ongoing debate. Objectives To elucidate the long-term clinical and neuropsychological effects of PLE and to find possible etiological correlates. Methods We retrospectively collected clinical and neuropsychological data from 51 PD patients before and one year after DBS. PLE visualized on FLAIR MRI sequence was manually segmented. Using appropriate statistical tests, continuous and categorical variables were compared between patients with and without PLE. A multivariate regression model was employed to analyze the contribution of clinical variables to edema volume changes. Results 68.62% of patients presented PLE at the immediate postoperative MRI. Patients with PLE were significantly older (p<0.001) and had more frequent postoperative confusion episodes (p=0.025). Furthermore, more MER (microelectrode recording) tracks (p<0.001) were used in patients with PLE. Multiple MER tracks were directly correlated with edema volume and were the only significant predictors of edema volume changes in a multivariate regression model. No differences were found in other clinical and neuropsychological variables. Conclusions PLE is a frequent post-surgical event and may cause transient postoperative confusion. It seems linked to older age and multiple MER tracks. Although it does not influence global motor and neuropsychological outcomes, PLE contributes to postoperative confusion episodes. To avoid PLE sequelae, using multiple MER tracks in older patients should be discouraged. Introduction Deep brain stimulation (DBS) has been widely proven to be effective for the treatment of movement disorders, such as Parkinson’s disease (PD), essential tremor and dystonia 1 . Being employed in clinical practice for over thirty years, DBS has been demonstrated to reduce motor fluctuations and refractory tremor and to improve PD patients’ quality of life 2 . Moreover, its role in the management of different neuropsychiatric disorders 3 has recently been investigated and DBS is currently approved to improve the symptoms related to drug-resistant obsessive-compulsive disorder 4 and epilepsy 5 , 6 . Although it is usually considered a safe procedure, complications related to DBS have been reported in the literature 7 . The most common are hemorrhages, infections and hardware-related malfunctions 8 . Peri-lead edema (PLE) is an underrecognized complication of DBS procedures 9 , with an increasing number of scientific reports raising awareness of this event in recent years 10 . PLE is defined as the presence of an edematous reaction around the DBS electrode 11 with a reported incidence between 0.4 and 6.9% 12 , 13 . In this context, our group prospectively evaluated a cohort of PD patients and described that all patients displayed PLE at brain MR several months after the implantation 14 . PLE is usually asymptomatic 15 , 16 , although cases of hyperacute neurological deterioration presenting with focal neurological deficits and seizures were reported 17 , 18 On the other hand, PLE did not appear to influence the neuropsychological profile of PD patients, at least on short-term follow-ups 13 . Given the currently unknown etiology of PLE and its poorly understood impact on long-term outcomes, this study aims to investigate the clinical and neuropsychological associations of PLE in PD patients undergoing DBS of the subthalamic nucleus (STN) at the last follow-up available. Then, we will try to find possible correlates of PLE formation. Materials and methods Patients’ selection and peri-lead volume estimation We retrospectively reviewed our institution’s clinical database and searched for PD patients who received bilateral STN-DBS and performed a brain MRI at least 24 hours after surgery. Fifty-one patients resulted from our search. For each patient, the following variables were collected: demographic data (sex, age at PD onset and implantation, educational level), clinical data (disease duration, L-Dopa [levodopa] dosage, LEDD [levodopa equivalent daily dose], MDS-UPDRS-III [Movement Disorder Society-Unified Parkinson’s Disease Rating Scale part III] score, the MoCA [Montreal Cognitive Assesment] total score and domain-specific sub-scores: memory, visuospatial abilities, executive functions, attention, language and orientation 19 , 20 ). Clinical variables were reported before and one year after the implantation. For each patient, MRI was screened for PLE, which was identified as signal hyperintensity surrounding the electrode on FLAIR MRI sequences. With the commercially available software BrainLab, PLE was manually segmented by two expert users and its volume was calculated. Segmentation results were checked by two experienced neurosurgeons. Then, patients were divided into two groups based on the presence or absence of PLE. All PD patients included in this study were followed up by attending neurologists and neuropsychologists with many years of experience in the field of movement disorders. The surgical procedures were performed by the same attending neurosurgeons at the Neurosurgery Department of our institution. Surgical procedure Our surgical technique consisted of a two-step procedure as previously described in other publications 21 , 22 . Briefly, the first step was conducted under local anaesthesia in the awake patient. Before surgery, a Cosman-Roberts-Wells stereotactic frame (Radionics by Integra, Plainsboro, New Jersey, USA) was placed on the patient’s head and a stereotactic CT scan was performed. A dedicated workstation (Istereotaxy by BrainLab, Kapellenstrat, Germany) was used to co-register the CT scan with the MRI performed the day before to plan STN surgical targeting. An MER (microelectrode recording) (microTargeting Electrode TM , FHC Inc, Bowdoin, Maine, USA) was inserted before lead implantation and the electrophysiologic activity of STN was tested. Then, the neurologist checked for possible side effects during intraoperative stimulation. In case of poor STN recording or side effects at low amplitude stimulation, a second MER track was tested. Finally, DBS leads (Model 3389 by Medtronic Inc., Minneapolis, Minnesota, USA) were implanted bilaterally. A second surgery was scheduled within seven days after the first one and performed under general anesthesia. During this surgical time, intracranial electrodes were elongated with lead extenders, which were then connected to an IPG Medtronic Activa PC implanted into a subcutaneous pouch in the right hemithorax. Patients were subsequently discharged and the stimulation was turned on three to six weeks after surgery during a second hospitalization. Statistical analysis Categorical variables were reported as absolute numbers and percentages, while continuous variables were reported as mean plus standard deviation. A Shapiro-Wilk normality test was used to assess the normality across selected variables along with a close inspection of the data plotted on histograms and Q-Q graphs. A Chi-Square test was used to compare categorical variables between patients with and without PLE. MANOVA was employed to perform multivariate comparisons between the two groups of patients. In this context, the Pillai-Bartlett trace (V) multivariate test was used as a test for overall statistical significance among all variables and ANOVA univariate F-statistic as a follow-up test in case of multivariate significance. Pearson’s correlation (r) was used to examine relationships between two continuous variables and standard multivariate regression to account for the possible effect of several clinical variables on the change of a chosen variable. Confidence intervals were bootstraped by 1000 samples. For all traditional hypotheses, p values < 0.05 were considered statistically significant. Statistical analysis was performed using SPSS (version 29.0, IBM). Results Overall patients’ demographics Fifty-one PD patients were included in this study and one hundred and two electrodes were implanted in STN bilaterally. Most patients were female (26/51, 51%). The mean PD duration before surgery and mean age at implantation were 11.53 ± 3.52 and 55.61 ± 10.07 years, respectively. The mean educational level – i.e., years spent for education purposes-was 12.5 ± 3.82. Other clinical and neuropsychological results from preoperative and one-year follow-up evaluations are reported in Table 1 . View this table: View inline View popup Download powerpoint Table 1: Clinical and neuropsychological variables measured at the baseline before the surgery and at a one-year follow-up visit After a mean postoperative time of 8.4 ± 6.37 days, the mean total PLE volume was 12.37 ± 14.85 mm 3 , while the mean total volume of hemorrhagic spots around the lead was 0.5 ± 1.75 mm 3 . There were no symptomatic hematomas requiring surgical treatment in our cohort. Edema groups comparison At the first postoperative MRI, 68.62% of patients (35/51) displayed PLE ( Figure 1 ). There were more females among patients with postoperative PLE (21/35, 60% VS 5/16, 31.3%; p=0.057). Postoperative confusion was more common in patients with PLE (9/35, 25.7% VS 0/16, 0%, p=0.025). Download figure Open in new tab Figure 1: Peri-lead edema on brain MRI after STN-DBS Illustrative case of an implanted patient displaying bilateral peri-lead edema at the first post-operative MRI scan. In the FLAIR sequence, the hyperintense signal surrounding the electrode is visible from the cortical surface to the deep white matter. Brain scan projections from left to right: axial, coronal and sagittal. When comparing clinical and neuropsychological evaluations between patients with and without edema, the multivariate test was statistically significant (V=0.83, F(24,26)=4.7, p<0.001). The follow-up univariate analysis showed that PLE patients were significantly older (p<0.001), received more MER tracks during surgery (p<0.001) and had lower dosages of parkinsonian drugs both before and after the implantation: L-Dopa pre-(p=0.002) and postoperative (p=0.037); LEDD pre-(p=0.016) and postoperative (p=0.002). No statistically significant differences were found for the other variables ( Table 2 ). View this table: View inline View popup Table 2: Comparison of the clinical and neuropsychological variables between patients with and without perielectrode edema. Predictors of edema volume The total edema volume was directly correlated with the number of MER tracks used (r = 0.65, 95% BCa CI [0.51, 0.8], p<0.001) and inversely correlated with antiparkinsonian drugs: preoperative L-Dopa (r = -0.312, 95% BCa CI [-0.5, -0.065], p=0.026), postoperative L-Dopa (r = -0.443, 95% BCa CI [-0.624, -0.233], p=0.001), postoperative LEDD (r = -0.404, 95% BCa CI [-0.58, -0.188], p=0.003) ( Figure 2 ). Download figure Open in new tab Figure 2: Correlation matrix and significance values from correlation analysis A: Correlation matrix showing Pearson’s correlation coefficient (r) from correlation analysis between significant variables and edema volume. On the right, the color-coded scale displays the strength of correlation. B : p values from each correlation. Note that only six correlations (enlightened in green) were statistically significant. MER: microelectrode recordings. L-Dopa: levodopa dosage in mg. LEDD: levodopa equivalent daily dose. However, the number of MER tracks was the only variable that significantly contributed to the model in a multiple regression analysis (adjusted R 2 = 0.408, F(1,49) = 35.47, p<0.001). Specifically, MER tracks explained 65% of the variance in edema volume (unstandardized B = 10.204 ± 1.713, β = 0.65, p<0.001, sr 2 = 0.65). Non-significant results from each regression analysis are reported in Supplementary Materials . Discussion We analyzed a retrospective cohort of PD patients displaying PLE after STN-DBS and demonstrated that edema had no impact on long-term clinical and neuropsychological outcomes. Nonetheless, the first post-operative MRI showed an edematous reaction around the electrodes in 68.62% of our patients. This result confirms an emerging trend from the current literature, i.e. PLE is a more frequent complication than originally described 12 , 23 . Several factors may contribute to the discrepancies observed in different studies. Firstly, the imaging modality used to identify PLE can influence the timely diagnosis of this complication. In fact, the first PLE reports were based on CT scans, which are routinely performed in many centers to verify the correct lead placement in the immediate postoperative period. However, it is now unanimously acknowledged that CT is less sensitive than MRI for PLE detection 24 . Furthermore, not all MRI sequences have the same characteristics and T2-weighted sequences can better delineate edematous reactions 25 . In this context, FLAIR is a T2 sequence acquired with an inversion time modality to negate the cerebrospinal fluid’s contribution to the magnetic signal, thus allowing a more precise characterization of fluid collections and edema 26 . Therefore, we decided to employ the FLAIR sequence to estimate PLE in our patients. Secondly, the timing of postoperative imaging acquisition seems to play a not negligible role in PLE identification. In one of the earliest PLE series, Englot et al. 27 observed that PLE was present in only 1% of patients at day-1 brain MRI, while PLE reached a 50% incidence if the MRI scan was performed between the 5th and 30th postoperative days. More recently, our group prospectively followed 19 consecutive PD patients after STN-DBS and demonstrated that all subjects had PLE in at least one hemisphere on consecutive MRI between the 7th and 20th postoperative days 14 . Nevertheless, we found no significant differences in postoperative MRI scheduling time between patients with and without PLE. This result underscores that PLE is not a simply radiological epiphenomenon, but it is influenced by patient- and surgery-related factors. The etiology of PLE remains unclear. While all studies agree on its non-infectious nature after extensive laboratory and imaging workup 28 , 29 , different theories have been formulated regarding the pathophysiology of PLE. Some authors sustained that PLE has an allergic or immune-mediated origin 30 . From this perspective, PLE would have been caused by a hypersensitivity reaction to some components of DBS electrodes or any of the materials employed during the surgery, i.e. irrigation solutions, firing glues or other dural sealants 31 , 32 . Furthermore, Servello et al. 33 even reported more frequent edematous reactions with leads from one vendor than others. However, this immune-mediated theory is not supported by the fact that PLE usually self-resolves without steroid therapy despite the persistence of the presumed offending agent and that many patients manifest unilateral brain edema even after bilateral procedures 27 . On the other hand, our results seem to point to the hypothesis of altered blood-brain barrier permeability 12 . According to this view, PLE would be due to mechanical mico-lesioning of the blood-brain barrier and subsequent transient increase of water filtering into the interstitial space 34 , 35 . In fact, we found that more MER tracks were used in PLE patients than in subjects without edema. Moreover, total edema volume was directly proportional to the total number of MERs, which also resulted in being the only significant predictor of edema volume after controlling for other clinical variables. Although the notion of a more frequent edematous reaction in patients undergoing MER has already been reported 13 , 36 , no authors presented statistically significant differences or correlations possibly because of the smaller cohorts in the previous series. Patients with PLE are usually asymptomatic and no pharmacological treatments are needed for this complication that is often purely radiologic 24 , 36 , 37 . However, reports exist regarding PLE patients presenting with mental state deterioration within hours after the implantation or with seizures 31 , 38 – 40 and focal neurological deficits along with MRI evidence of cavitation reaction accompanying PLE 18 . In these cases, symptoms regressed after steroid administration 41 . In our cohort, 26% of PLE patients experienced transient episodes of confusion. Usually beginning between 24 and 48 hours after the implantation, this cognitive alteration consisted of a variable mixture of thought slowdown, space and time disorientation and decreased motor initiative. These episodes were self-resolving and did not need medical therapy. However, this subset of PLE patients had a longer hospital stay for further observation. Together with edema volume, the patient’s age at the implantation was another significant difference between patients with and without edema. Indeed, PLE patients in our cohort were significantly older than patients without edema, although the patient’s age did not significantly correlate with edema volume. In a similar study, Giordano et al. 13 also used advanced patient age to support the hypothesis of mechanical damage for PLE pathogenesis, i.e. older brain tissue is more fragile and more prone to enhanced vasogenic and inflammatory responses to surgical insults 42 , 43 . In this context, multiple brain penetration with MER tracks assumes further importance in the possible PLE etiology. Although the usage of more than one MER is linked to clinically relevant brain haemorrhages 7 , 44 , our patients only presented small hemorrhagic spots, which were clinically silent and no statistically significant differences in hemorrhagic spots resulted between the two patient groups. These findings may be explained if we consider multiple MERs as a necessary but not sufficient factor for PLE occurrence, since other variables – such as advanced age – may contribute. Finally, we found no differences in long-term motor and neuropsychological outcomes between PLE patients and those without edema in accordance with previous studies 23 , 45 . In fact, DBS was demonstrated not to alter the long-term cognitive profiles of PD patients compared to not-implanted PD controls 46 , 47 . Limitations The main limitation of our work is its retrospective nature, which may lead to selection bias. While the monocentric nature of our study grants that all patients were treated and followed homogeneously, our results may not be fully generalizable because of some slight differences in surgical technique existing among centers. Furthermore, we implanted the previous model of omnidirectional DBS leads, since the latest directional leads were only recently introduced in our country. In clinical practice, adopting directional leads reduced the need for multiple MERs for some centers or completely abolished their usage for others 48 – 50 . By so doing, this technical advance would remove one of the PLE risk factors identified in our study. However, the stringent need for MER in DBS procedures is still a matter of debate 51 , 52 and prominent groups still sustain the importance of a precise neurophysiological delineation of the target nucleus by MER mapping before permanent electrode implantation 53 , 54 . Nonetheless, the relationship between directional leads and PLE deserves further investigation and will be the subject of subsequent studies by our group. In this study, we presented a retrospective cohort of PD patients displaying PLE after STN-DBS and suffering from transient postoperative confusion. We also described the influence of multiple MER tracks on PLE and postulated an important causative role related to it. Based on our results, we suggest limiting the number of MER tracks in older patients, who are known to be prone to delirium and altered mental status after surgical procedures 55 . In fact, several brain penetrations seem to be related to PLE, which causes postoperative confusion with longer hospitalization. Data Availability All data produced in the present study are available upon reasonable request to the authors References 1. ↵ Lee DJ , Lozano CS , Dallapiazza RF , Lozano AM . Current and future directions of deep brain stimulation for neurological and psychiatric disorders . J Neurosurg . 2019 ; 131 ( 2 ): 333 – 342 . doi: 10.3171/2019.4.JNS181761 OpenUrl CrossRef PubMed 2. ↵ Bove F , Mulas D , Cavallieri F , et al. Long-term outcomes (15 years) after subthalamic nucleus deep brain stimulation in patients with Parkinson disease . Neurology . 2021 ; 97 ( 3 ): e254 – e262 . OpenUrl PubMed 3. ↵ Johnson KA , Dosenbach NUF , Gordon EM , et al. Proceedings of the 11th Annual Deep Brain Stimulation Think Tank: pushing the forefront of neuromodulation with functional network mapping, biomarkers for adaptive DBS, bioethical dilemmas, AI-guided neuromodulation, and translational advancements . Front Hum Neurosci . 2024 ; 18 . doi: 10.3389/fnhum.2024.1320806 OpenUrl CrossRef 4. ↵ Mar-Barrutia L , Real E , Segalás C , Bertolín S , Menchón JM , Alonso P . Deep brain stimulation for obsessive-compulsive disorder: A systematic review of worldwide experience after 20 years . World J Psychiatry . 2021 ; 11 ( 9 ): 659 – 680 . doi: 10.5498/wjp.v11.i9.659 OpenUrl CrossRef PubMed 5. ↵ Fisher R , Salanova V , Witt T , et al. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy . Epilepsia . 2010 ; 51 ( 5 ): 899 – 908 . doi: 10.1111/j.1528-1167.2010.02536.x OpenUrl CrossRef PubMed Web of Science 6. ↵ Remore LG , Omidbeigi M , Tsolaki E , Bari AA . Deep brain stimulation of thalamic nuclei for the treatment of drug-resistant epilepsy: Are we confident with the precise surgical target? Seizure . 2023 ; 105 : 22 – 28 . doi: 10.1016/j.seizure.2023.01.009 OpenUrl CrossRef PubMed 7. ↵ Zrinzo L , Foltynie T , Limousin P , Hariz MI . Reducing hemorrhagic complications in functional neurosurgery: A large case series and systematic literature review - Clinical article . J Neurosurg . 2012 ; 116 ( 1 ): 84 – 94 . doi: 10.3171/2011.8.JNS101407 OpenUrl CrossRef PubMed Web of Science 8. ↵ Patel DM , Walker HC , Brooks R , Omar N , Ditty B , Guthrie BL . Adverse events associated with deep brain stimulation for movement disorders: Analysis of 510 consecutive cases . Operative Neurosurgery . 2015 ; 11 ( 1 ): 200 . doi: 10.1227/NEU.0000000000000659 OpenUrl CrossRef 9. ↵ Lefaucheur R , Derrey S , Borden A , et al. Post-operative edema surrounding the electrode: An unusual complication of deep brain stimulation . Brain Stimul . 2013 ; 6 ( 3 ): 459 – 460 . doi: 10.1016/j.brs.2012.05.012 OpenUrl CrossRef PubMed 10. ↵ Whiting AC , Catapano JS , Walker CT , Godzik J , Lambert M , Ponce FA . Peri-Lead Edema After Deep Brain Stimulation Surgery: A Poorly Understood but Frequent Complication . World Neurosurg . 2019 ; 124 : e340 – e345 . doi: 10.1016/j.wneu.2018.12.092 OpenUrl CrossRef 11. ↵ Saitoh T , Enatsu R , Mikami T , et al. Peri-electrode edema after deep brain stimulation . Journal of Clinical Neuroscience . 2019 ; 59 : 29 – 31 . doi: 10.1016/j.jocn.2018.11.026 OpenUrl CrossRef PubMed 12. ↵ Kim JW , Hwang JH , Kim IK , et al. Acute brain reaction to DBS electrodes after deep brain stimulation: Chronological observation . Acta Neurochir (Wien ) . 2013 ; 155 ( 12 ): 2365 – 2371 . doi: 10.1007/s00701-013-1853-3 OpenUrl CrossRef PubMed 13. ↵ Giordano M , Innocenti N , Rizzi M , et al. Incidence and management of idiopathic peri-lead edema (IPLE) following deep brain stimulation (DBS) surgery: Case series and review of the literature . Clin Neurol Neurosurg . 2023 ; 234 . doi: 10.1016/j.clineuro.2023.108009 OpenUrl CrossRef 14. ↵ Borellini L , Ardolino G , Carrabba G , et al. Peri-lead edema after deep brain stimulation surgery for Parkinson’s disease: a prospective magnetic resonance imaging study . Eur J Neurol . 2019 ; 26 ( 3 ): 533 – 539 . doi: 10.1111/ene.13852 OpenUrl CrossRef PubMed 15. ↵ Habibi SAH , Shahidi G , Parvaresh M , et al. Cerebral peri-lead edema following deep brain stimulation surgery . Neurological Sciences . 2020 ; 41 ( 2 ): 473 – 475 . doi: 10.1007/s10072-019-04042-8 OpenUrl CrossRef 16. ↵ Prenassi M , Borellini L , Bocci T , et al. Peri-lead edema and local field potential correlation in post-surgery subthalamic nucleus deep brain stimulation patients . Front Hum Neurosci . 2022 ; 16 . doi: 10.3389/fnhum.2022.950434 OpenUrl CrossRef 17. ↵ Fenoy AJ , Conner CR , Withrow JS , Hocher AW . Case report of hyperacute edema and cavitation following deep brain stimulation lead implantation . Surg Neurol Int . 2020 ; 11 . doi: 10.25259/SNI_527_2019 OpenUrl CrossRef 18. ↵ Fenoy AJ , Villarreal SJ , Schiess MC . Acute and subacute presentations of cerebral edema following deep brain stimulation lead implantation . Stereotact Funct Neurosurg . 2017 ; 95 ( 2 ): 86 – 92 . doi: 10.1159/000454892 OpenUrl CrossRef PubMed 19. ↵ Santangelo G , Siciliano M , Pedone R , et al. Normative data for the Montreal Cognitive Assessment in an Italian population sample . Neurological Sciences . 2015 ; 36 : 585 – 591 . OpenUrl CrossRef PubMed 20. ↵ Nasreddine ZS , Phillips NA , Bédirian V , et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment . J Am Geriatr Soc . 2005 ; 53 ( 4 ): 695 – 699 . OpenUrl CrossRef PubMed Web of Science 21. ↵ Remore LG , Tariciotti L , Fiore G , et al. The role of SWI sequence during the preoperative targeting of the subthalamic nucleus for deep brain stimulation in Parkinson’s disease: A retrospective cohort study . World Neurosurg X . Published online March 2024 : 100342 . doi: 10.1016/j.wnsx.2024.100342 OpenUrl CrossRef 22. ↵ Mameli F , Ruggiero F , Dini M , et al. Energy Delivered by Subthalamic Deep Brain Stimulation for Parkinson Disease Correlates With Depressive Personality Trait Shift . Neuromodulation . Published online 2022 . doi: 10.1016/j.neurom.2022.01.004 OpenUrl CrossRef 23. ↵ Sharma VD , Lyons KE , Nazzaro JM , Pahwa R . Does post-operative symptomatic lead edema associated with subthalamic DBS implantation impact long-term clinical outcomes? J Neurol Sci . 2020 ; 410 . doi: 10.1016/j.jns.2019.116647 OpenUrl CrossRef 24. ↵ Succop BS , Zamora C , Roque DA , Hadar E , Kessler B , Quinsey C . Day one postoperative MRI findings following electrode placement for deep brain stimulation: analysis of a large case series . Front Neurol . 2023 ; 14 . doi: 10.3389/fneur.2023.1253241 OpenUrl CrossRef 25. ↵ Lu CY , Chiang IC , Lin WC , Kuo YT , Liu GC . Detection of intracranial hemorrhage . Clin Imaging . 2005 ; 29 ( 3 ): 155 – 161 . doi: 10.1016/j.clinimag.2004.07.024 OpenUrl CrossRef PubMed 26. ↵ Bakshi R , Ariyaratana S , Benedict RHB , Jacobs L . Fluid-Attenuated Inversion Recovery Magnetic Resonance Imaging Detects Cortical and Juxtacortical Multiple Sclerosis Lesions . Arch Neurol . 2001 ; 58 ( 5 ): 742 . doi: 10.1001/archneur.58.5.742 OpenUrl CrossRef PubMed Web of Science 27. ↵ Englot DJ , Glastonbury CM , Larson PS . Abnormal T2-weighted MRI signal surrounding leads in a subset of deep brain stimulation patients . Stereotact Funct Neurosurg . 2011 ; 89 ( 5 ): 311 – 317 . doi: 10.1159/000329365 OpenUrl CrossRef PubMed 28. ↵ Arocho-Quinones E V. , Pahapill PA . Non-Infectious Peri-Electrode Edema and Contrast Enhancement Following Deep Brain Stimulation Surgery . Neuromodulation . 2016 ; 19 ( 8 ): 872 – 876 . doi: 10.1111/ner.12432 OpenUrl CrossRef PubMed 29. ↵ Nazzaro JM , Pahwa R , Lyons KE . Symptomatic, non-infectious, non-hemorrhagic edema after subthalamic nucleus deep brain stimulation surgery for Parkinson’s disease . J Neurol Sci . 2017 ; 383 : 42 – 46 . doi: 10.1016/j.jns.2017.10.003 OpenUrl CrossRef PubMed 30. ↵ Kozai TDY , Jaquins-Gerstl AS , Vazquez AL , Michael AC , Cui XT . Brain tissue responses to neural implants impact signal sensitivity and intervention strategies . ACS Chem Neurosci . 2015 ; 6 ( 1 ): 48 – 67 . doi: 10.1021/cn500256e OpenUrl CrossRef PubMed 31. ↵ Schoen NB , Jermakowicz WJ , Luca CC , Jagid JR . Acute symptomatic peri-lead edema 33 hours after deep brain stimulation surgery: a case report . J Med Case Rep . 2017 ; 11 ( 1 ). doi: 10.1186/s13256-017-1275-6 OpenUrl CrossRef 32. ↵ de Cuba CMKE , Albanese A , Antonini A , et al. Idiopathic delayed-onset edema surrounding deep brain stimulation leads: Insights from a case series and systematic literature review . Parkinsonism Relat Disord . 2016 ; 32 : 108 – 115 . doi: 10.1016/j.parkreldis.2016.09.007 OpenUrl CrossRef PubMed 33. ↵ Servello D , Galbiati TF , Iess G , Minafra B , Porta M , Pacchetti C . Complications of deep brain stimulation in Parkinson’s disease: a single-center experience of 517 consecutive cases . Acta Neurochir (Wien ) . 2023 ; 165 ( 11 ): 3385 – 3396 . doi: 10.1007/s00701-023-05799-w OpenUrl CrossRef PubMed 34. ↵ Nolt MJ , Polasani RS , Masnyk TW , Rezak M , Rosenow JM . Prospective Evaluation of the Time Course of White Matter Edema Associated with Implanted Deep Brain Stimulation Electrodes . Stereotact Funct Neurosurg . 2021 ; 99 ( 3 ): 203 – 206 . doi: 10.1159/000511115 OpenUrl CrossRef PubMed 35. ↵ Ryu SI , Romanelli P , Heit G . Asymptomatic transient MRI signal changes after unilateral deep brain stimulation electrode implantation for movement disorder . Stereotact Funct Neurosurg . 2004 ; 82 ( 2-3 ): 65 – 69 . doi: 10.1159/000077402 OpenUrl CrossRef PubMed 36. ↵ Staudt MD , MacDougall KW . Spontaneous Regression of an Intraparenchymal Cyst Following Deep Brain Stimulator Electrode Implantation: Case Report and Literature Review . World Neurosurg . 2018 ; 117 : 249 – 254 . doi: 10.1016/j.wneu.2018.06.115 OpenUrl CrossRef PubMed 37. ↵ Fernández-Pajarín G , Sesar A , Ares B , et al. Delayed complications of deep brain stimulation: 16-year experience in 249 patients . Acta Neurochir (Wien ) . 2017 ; 159 ( 9 ): 1713 – 1719 . doi: 10.1007/s00701-017-3252-7 OpenUrl CrossRef PubMed 38. ↵ Lee JJ , Daniels B , Austerman RJ , Dalm BD . Symptomatic, left-sided deep brain stimulation lead edema 6 h after bilateral subthalamic nucleus lead placement . Surg Neurol Int . 2019 ; 10 ( 68 ): 1 – 4 . doi: 10.25259/SNI-125-2019 OpenUrl CrossRef PubMed 39. Domino JS , Lundy P , Kaufman CB . Fulminant non-infectious peri-electrode edema after deep brain stimulation system implantation in a pediatric patient . Child’s Nervous System . 2022 ; 38 ( 2 ): 447 – 454 . doi: 10.1007/s00381-021-05224-6 OpenUrl CrossRef PubMed 40. ↵ Gerard CS , Metman LV , Pal G , Karl J , Sani S . Severe, symptomatic, self-limited unilateral DBS lead edema following bilateral subthalamic nucleus implantation: Case report and review of the literature . Neurologist . 2016 ; 21 ( 4 ): 58 – 60 . doi: 10.1097/NRL.0000000000000082 OpenUrl CrossRef PubMed 41. ↵ Wu B , Ling Y , Zhang C , et al. Postoperative use of steroids for peri-electrode edema after deep brain stimulation surgery: A retrospective cohort study . CNS Neurosci Ther . 2024 ; 30 ( 3 ). doi: 10.1111/cns.14470 OpenUrl CrossRef 42. ↵ Wakim AA , Mattar JB , Lambert M , Ponce FA . Perioperative complications of deep brain stimulation among patients with advanced age: a single-institution retrospective analysis . In: Journal of Neurosurgery . Vol 135 . American Association of Neurological Surgeons; 2021 : 1421 - 1428 . doi: 10.3171/2020.8.JNS201283 OpenUrl CrossRef PubMed 43. ↵ Bautmans I , Njemini R , De Backer J , De Waele E , Mets T . Surgery-induced inflammation in relation to age, muscle endurance, and self-perceived fatigue . Journals of Gerontology - Series A Biological Sciences and Medical Sciences . 2010 ; 65 A( 3 ): 266 – 273 . doi: 10.1093/gerona/glp145 OpenUrl CrossRef PubMed Web of Science 44. ↵ Rasiah NP , Maheshwary R , Kwon CS , Bloomstein JD , Girgis F . Complications of Deep Brain Stimulation for Parkinson Disease and Relationship between Micro-electrode tracks and hemorrhage: Systematic Review and Meta-Analysis . World Neurosurg . 2023 ; 171 : e8 – e23 . doi: 10.1016/j.wneu.2022.10.034 OpenUrl CrossRef PubMed 45. ↵ Nishiguchi Y , Matsuura K , Hirata Y , et al. Relationship of brain edema after deep brain stimulation surgery with motor and cognitive function . Heliyon . 2022 ; 8 ( 2 ). doi: 10.1016/j.heliyon.2022.e08900 OpenUrl CrossRef 46. ↵ Contarino MF , Daniele A , Sibilia AH , et al. Cognitive outcome 5 years after bilateral chronic stimulation of subthalamic nucleus in patients with Parkinson’s disease . J Neurol Neurosurg Psychiatry . 2007 ; 78 ( 3 ): 248 – 252 . doi: 10.1136/jnnp.2005.086660 OpenUrl Abstract / FREE Full Text 47. ↵ Kim HJ , Jeon BS , Paek SH , et al. Long-term cognitive outcome of bilateral subthalamic deep brain stimulation in Parkinson’s disease . J Neurol . 2014 ; 261 ( 6 ): 1090 – 1096 . doi: 10.1007/s00415-014-7321-z OpenUrl CrossRef PubMed 48. ↵ Frey J , Cagle J , Johnson KA , et al. Past, Present, and Future of Deep Brain Stimulation: Hardware, Software, Imaging, Physiology and Novel Approaches . Front Neurol . 2022 ; 13 . doi: 10.3389/fneur.2022.825178 OpenUrl CrossRef PubMed 49. Krauss JK , Lipsman N , Aziz T , et al. Technology of deep brain stimulation: current status and future directions . Nat Rev Neurol . 2021 ; 17 ( 2 ): 75 – 87 . OpenUrl PubMed 50. ↵ Schulder M , Mishra A , Mammis A , et al. Advances in Technical Aspects of Deep Brain Stimulation Surgery . Stereotact Funct Neurosurg . 2023 ; 101 ( 2 ): 112 – 134 . doi: 10.1159/000529040 OpenUrl CrossRef PubMed 51. ↵ Aziz TZ , Hariz M . To sleep or not to sleep during deep brain stimulation surgery for Parkinson disease? Neurology . 2017 ; 89 ( 19 ): 1938 – 1939 . doi: 10.1212/WNL.0000000000004635 OpenUrl CrossRef PubMed 52. ↵ Pastor J , Vega-Zelaya L . Can we put aside microelectrode recordings in deep brain stimulation surgery? Brain Sci . 2020 ; 10 ( 9 ): 1 – 4 . doi: 10.3390/brainsci10090571 OpenUrl CrossRef 53. ↵ Lozano CS , Ranjan M , Boutet A , et al. Imaging alone versus microelectrode recording–guided targeting of the STN in patients with Parkinson’s disease . J Neurosurg . 2019 ; 1306 ( 6 ): 1847 – 1852 . doi: 10.3171/2018.2.JNS172186 OpenUrl CrossRef 54. ↵ Runge J , Nagel JM , Schrader C , et al. Microelectrode recording and hemorrhage in functional neurosurgery: a comparative analysis in a consecutive series of 645 procedures . J Neurosurg . 2024 ; 140 ( 5 ): 1442 – 1450 . doi: 10.3171/2023.8.JNS23613 OpenUrl CrossRef PubMed 55. ↵ Segal-Gidan F . Postoperative confusion in older adults . J Am Acad Physician Assist . 2017 ; 30 ( 4 ): 12 – 16 . doi: 10.1097/01.JAA.0000513345.29384.39 OpenUrl CrossRef View the discussion thread. Back to top Previous Next Posted May 05, 2025. Download PDF Supplementary Material Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Peri-Lead Edema in Deep Brain Stimulation: Long-Term Outcomes and Possible Etiological Correlates Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Peri-Lead Edema in Deep Brain Stimulation: Long-Term Outcomes and Possible Etiological Correlates Luigi G. Remore , Giorgio Fiore , Elena Pirola , Linda Borellini , Francesca Mameli , Fabiana Ruggiero , Eleonora Zirone , Roberta Ferrucci , Filippo Cogiamanian , Enrico Mailland , Antonella M. Ampollini , Giulio A. Bertani , Stefania E. Navone , Giovanni Marfia , Ioannis U. Isaias , Marco Locatelli medRxiv 2025.05.01.25326737; doi: https://doi.org/10.1101/2025.05.01.25326737 Share This Article: Copy Citation Tools Peri-Lead Edema in Deep Brain Stimulation: Long-Term Outcomes and Possible Etiological Correlates Luigi G. Remore , Giorgio Fiore , Elena Pirola , Linda Borellini , Francesca Mameli , Fabiana Ruggiero , Eleonora Zirone , Roberta Ferrucci , Filippo Cogiamanian , Enrico Mailland , Antonella M. Ampollini , Giulio A. Bertani , Stefania E. Navone , Giovanni Marfia , Ioannis U. Isaias , Marco Locatelli medRxiv 2025.05.01.25326737; doi: https://doi.org/10.1101/2025.05.01.25326737 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Neurology Subject Areas All Articles Addiction Medicine (568) Allergy and Immunology (863) Anesthesia (300) Cardiovascular Medicine (4435) Dentistry and Oral Medicine (444) Dermatology (382) Emergency Medicine (608) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1509) Epidemiology (15229) Forensic Medicine (30) Gastroenterology (1124) Genetic and Genomic Medicine (6600) Geriatric Medicine (668) Health Economics (997) Health Informatics (4538) Health Policy (1368) Health Systems and Quality Improvement (1613) Hematology (541) HIV/AIDS (1264) Infectious Diseases (except HIV/AIDS) (15916) Intensive Care and Critical Care Medicine (1103) Medical Education (623) Medical Ethics (146) Nephrology (667) Neurology (6599) Nursing (346) Nutrition (998) Obstetrics and Gynecology (1144) Occupational and Environmental Health (957) Oncology (3333) Ophthalmology (974) Orthopedics (369) Otolaryngology (420) Pain Medicine (436) Palliative Medicine (130) Pathology (663) Pediatrics (1693) Pharmacology and Therapeutics (691) Primary Care Research (711) Psychiatry and Clinical Psychology (5447) Public and Global Health (9232) Radiology and Imaging (2198) Rehabilitation Medicine and Physical Therapy (1370) Respiratory Medicine (1196) Rheumatology (593) Sexual and Reproductive Health (712) Sports Medicine (530) Surgery (712) Toxicology (99) Transplantation (289) Urology (265) (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'a00d378cf8241640',t:'MTc3OTYzNTMxOQ=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();