key: cord-0808276-vms39628
authors: Ineichen, Benjamin V.; Tsagkas, Charidimos; Absinta, Martina; Reich, Daniel S.
title: Leptomeningeal enhancement in multiple sclerosis and other neurological diseases: A systematic review and Meta-Analysis
date: 2022-01-10
journal: Neuroimage Clin
DOI: 10.1016/j.nicl.2022.102939
sha: 1cb501d04886474ebb65dd97da2d7e51a0a0c071
doc_id: 808276
cord_uid: vms39628

BACKGROUND: The lack of systematic evidence on leptomeningeal enhancement (LME) on MRI in neurological diseases, including multiple sclerosis (MS), hampers its interpretation in clinical routine and research settings. PURPOSE: To perform a systematic review and meta-analysis of MRI LME in MS and other neurological diseases. MATERIALS AND METHODS: In a comprehensive literature search in Medline, Scopus, and Embase, out of 2292 publications, 459 records assessing LME in neurological diseases were eligible for qualitative synthesis. Of these, 135 were included in a random-effects model meta-analysis with subgroup analyses for MS. RESULTS: Of eligible publications, 161 investigated LME in neoplastic neurological (n = 2392), 91 in neuroinfectious (n = 1890), and 75 in primary neuroinflammatory diseases (n = 4038). The LME-proportions for these disease classes were 0.47 [95%-CI: 0.37–0.57], 0.59 [95%-CI: 0.47–0.69], and 0.26 [95%-CI: 0.20–0.35], respectively. In a subgroup analysis comprising 1605 MS cases, LME proportion was 0.30 [95%-CI 0.21–0.42] with lower proportions in relapsing-remitting (0.19 [95%-CI 0.13–0.27]) compared to progressive MS (0.39 [95%-CI 0.30–0.49], p = 0.002) and higher proportions in studies imaging at 7 T (0.79 [95%-CI 0.64–0.89]) compared to lower field strengths (0.21 [95%-CI 0.15–0.29], p < 0.001). LME in MS was associated with longer disease duration (mean difference 2.2 years [95%-CI 0.2–4.2], p = 0.03), higher Expanded Disability Status Scale (mean difference 0.6 points [95%-CI 0.2–1.0], p = 0.006), higher T1 (mean difference 1.6 ml [95%-CI 0.1–3.0], p = 0.04) and T2 lesion load (mean difference 5.9 ml [95%-CI 3.2–8.6], p < 0.001), and lower cortical volume (mean difference −21.3 ml [95%-CI −34.7–-7.9], p = 0.002). CONCLUSIONS: Our study provides high-grade evidence for the substantial presence of LME in MS and a comprehensive panel of other neurological diseases. Our data could facilitate differential diagnosis of LME in clinical settings. Additionally, our meta-analysis corroborates that LME is associated with key clinical and imaging features of MS. PROSPERO No: CRD42021235026.

enhancement (LME), which follows the pia-arachnoid abutting the cortical surface and extending into the sulci. LME is often caused by neoplastic or infectious processes. However, LME is also gaining attention as a putative imaging biomarker of meningeal inflammation in neuroinflammatory diseases, including MS and neurosarcoidosis ( Fig. 1 ) (Zurawski et al., 2017) .

Because LME can be present in a wide variety of neurological diseases (Absinta et al., 2017) , differential diagnostic considerations are paramount for proper patient workup. However, there is a lack of systematic evidence on LME proportions in MS and other neurological diseases. Furthermore, a wide variety of methodological approaches to imaging LME has been published (Singh et al., 2000; Zivadinov et al., 2018) , impeding the implementation of an appropriate imaging protocol for sensitive LME detection. With respect to MS, several studies have presented conflicting findings regarding the association of LME with clinical and imaging parameters (Absinta and Ontaneda, 2020 ), such that high-level evidence would benefit clinicians and researchers.

Based on these shortcomings, we set out to systematically summarize the available evidence on LME in neurological diseases with a focus on MS. This study had the following goals: (1) synthesize data on LME proportions in neurological diseases, including potentially distinct LME features such as phenotype or temporal evolution; (2) qualitatively and quantitatively summarize the potential association of LME with clinical and imaging features in MS; (3) propose an appropriate imaging protocol to detect LME in clinical and research practice; (4) summarize available data on pathological correlates of LME in neuroinflammation; (5) summarize available evidence on LME in animal models of neuroinflammation.

We registered the study protocol in the International prospective Fig. 1 . Leptomeningeal enhancement (LME) across the spectrum of neurological diseases. Leptomeningeal enhancement (LME, white arrows) can be detected using post-gadolinium fluid-attenuated inversion recovery (FLAIR) T2-weighted magnetic resonance imaging and can be present in viral diseases such as HIV (A, at 3 T), in primary neuroinflammatory diseases such as Susac syndrome (B, at 3 T) and multiple sclerosis (C, at 7 T), and in aseptic meningitis (natalizumab-induced) (D, at 3 T).

register of systematic reviews (PROSPERO, CRD42021235026, https:// www.crd.york.ac.uk/PROSPERO/) and used the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Guidelines for reporting (Moher et al., 2015) .

We searched for original studies published in full up to February 2, 2021, in PubMed, Scopus, and Ovid EMBASE. See Table S1 for the search string in each of these databases.

We included publications on human or animal data that reported on any outcome related to leptomeningeal inflammation on magnetic resonance imaging (MRI) in any neurological diseases. Case reports were also included in the systematic review. Exclusion criteria: conference abstracts, non-English articles, and publications that reiterated previously reported quantitative data. Reviews were excluded but retained as potential sources of additional records.

Titles and abstracts of studies were screened for their relevance in the web-based application Rayyan by two reviewers (CT and BVI), followed by full-text screening (Ouzzani et al., 2016) . Subsequently, the following data were extracted: title, authors, publication year, study design, neurological disease, and number of subjects per group. For studies with ≥ 10 subjects, MRI sequences/field strength, LME location (spinal cord, convexities, basal, cerebellar, brainstem), main study findings (in narrative manner), pattern of LME (for example, nodular or linear), temporal dynamics of LME, and proportions of LME in experimental and control groups were also extracted. For missing data on MRI sequences to detect LME, corresponding authors of respective publications were contacted. In total, 41 e-mails were sent out, and the response rate was 27% (11 response e-mails).

The quality of each study with ≥ 10 included subjects was assessed against predefined criteria by two reviewers (CT and BVI) using the Newcastle-Ottawa scale for evaluating risk of bias in nonrandomized studies (Wells et al., 2015) . Discrepancies were resolved by discussion.

Only diseases/disease classes with ≥ 2 publications describing ≥ 10 adult subjects each were included in the meta-analysis, and only summary-level data were used. As primary outcome, log-transformed proportions of LME were used. A random-effects model was fitted to the data. The amount of heterogeneity (τ2), was estimated using the DerSimonian-Laird estimator (DerSimonian and Laird, 1986) . In addition, the Q-test for heterogeneity (Cochran, 1954) and the I 2 statistic (Higgins and Thompson, 2002) are reported.

For subgroup analyses of clinical and imaging outcomes in MS, the analysis was carried out using the log-transformed proportions or mean difference as the outcome measure. Subgroup analyses were computed for MS to assess the proportion of LME in clinical MS phenotypes when ≥ 3 studies were available. Subgroup analyses in MS for clinical and imaging outcomes were computed when ≥ 3 studies reported at least mean, variance, and n for LME + and LME-groups on respective outcomes.

A two-tailed P value < 0.05 was considered statistically significant.

The rank correlation test and the regression test, using the standard error of the observed outcomes as predictor, were used to check for funnel plot asymmetry. The analysis was carried out using R (version 3.6.1) with the meta and metafor packages (version 2.4.0) (Viechtbauer, 2010) .

In total, 2292 original publications were retrieved from our comprehensive database search and an additional 10 publications from reference lists of reviews on related topics. After abstract and title screening, 1089 studies were eligible for full-text search. After screening the full text of these studies, 458 articles (35% of deduplicated references) were included for qualitative synthesis and 135 articles (10%) for quantitative synthesis (Figure S1 ).

Of the eligible publications, 144 investigated LME in neoplastic neurological diseases (2392 subjects including 183 children), 91 in infectious neurological diseases (1890 subjects including 48 children), and 76 in primary neuroinflammatory diseases (4038 subjects including 11 children). Additionally, 147 publications assessed LME in neurological diseases that did not belong to aforementioned categories (1961 subjects including 762 children). We also included 5 publications in animal models of neurological diseases (experimental autoimmune encephalomyelitis [EAE] in mice, bacterial meningitis in rats, bacterial CNS infection in a dog, subarachnoid diverticulum in a cat).

Most studies showed a low risk of bias for the selection domain (that is, whether patients and controls were defined according to acknowledged diagnostic criteria); see Table S2 and S3. Many studies did not report on adjusting their statistical analyses for subject age, sex, or other potential confounders (comparability domain), thus potentially inducing biases.

3.3.1. Primary neuroinflammatory diseases overall 3.3.1.1. Diseases. Studies reporting on LME in neuroinflammatory diseases were in neurosarcoidosis (20 publications), MS (17 publications), MOG-antibody diseases/encephalitis (8 publications), neuromyelitis optica spectrum disorder (NMOSD) (8 publications), primary angiitis of the CNS (6 publications), Susac syndrome (5 publications), anti-NMDAreceptor encephalitis (4 publications), Behçet syndrome (1 publication), and GFAP astrocytopathy (1 publication).

3.3.1.2. LME pattern. 21 studies did not report on the LME pattern, whereas the remaining studies reported on different LME patterns. The pattern of LME has most extensively been described in MS in 12 publications, mostly as either nodular and/or laminar/spread-and-fill. (Harrison et al., 2017b; Hildesheim et al., 2020; Ighani et al., 2020; Makshakov et al., 2017; Titelbaum et al., 2020; Zivadinov et al., 2017; Zurawski et al., 2020 ) Similar LME patterns have been described in Susac syndrome (Coulette et al., 2019) and neurosarcoidosis. (Junger et al., 1993; O'Connell et al., 2017) A spreading/laminar phenotype has been described in NMOSD, (Asgari et al., 2017; Fan et al., 2016; long et al., 2014) anti-NMDA-receptor encephalitis, (Neo et al., 2020) and GFAP astrocytopathy. (Dubey et al., 2018) 3.3.1.3. MRSI acquisition of LME. Most studies employed a postcontrast T2w-FLAIR sequence to visualize LME (19 publications) followed by a postcontrast T1w sequence (7 publications). 10 studies did not report the sequences used to detect LME.

A meta-analysis of LME in primary neuroinflammatory diseases, including a total of 2284 patients, showed an overall proportion of 0.26 [95%-CI: 0.20-0.35] with substantial heterogeneity across studies (I 2 = 90%, p < 0.001) (Fig. 2) . NMOSD had the lowest proportion of LME with 0.06 [95%-CI 0.02-0.23], and neurosarcoidosis had the highest LME proportion with 0.41 [95%-CI 0.13-0.52].

3.3.2.1. LME proportion in MS and subgroups. Two studies from 2015 first described LME in MS (Absinta et al., 2017; Eisele et al., 2015) .

Forest plot of leptomeningeal enhancement (LME) proportions in primary neuroinflammatory diseases. Pooled analyses of studies comparing the proportion of LME on MRI in neuroinflammatory diseases, stratified by diseases. Static magnetic field strength for MRI acquisition for respective studies are listed in brackets if reported. Proportions for LME were extracted and pooled using the random effects DerSimonian-Laird method. Abbreviations: CNS, central nervous system; CI, confidence interval; NMOSD, neuromyelitis optica spectrum disorder.

These and subsequent studies comprised 1605 MS patients, 303 non-MS controls, and 126 healthy controls ( Table 1) .

The overall proportion of LME in MS was 0.30 [95%-CI 0.21-0.42] (Fig. 3) . However, LME proportions in MS patients with a relapsingremitting clinical phenotype (0.19 [95%-CI 0.13-0.27]; 7 publications) and CIS patients (0.06 [95%-CI 0.02-0.20]; 3 publications) were significantly lower compared to progressive MS patients (0.39 [95%-CI 0.30-0.49], p = 0.002 and p = 0.003, respectively; 6 publications).

3.3.2.2. MRI acquisition of LME. 14 studies acquired MRI at 3 T (or complementing 1.5 T) and 3 studies at 7 T (Harrison et al., 2017b; Ighani et al., 2020; Zurawski et al., 2020) . In a meta-subgroup-analysis with the B 0 magnetic field strength as moderator, LME proportions were higher in studies imaging at 7 T (0.79 [95%-CI 0.64-0.89]; 3 publications) compared to studies imaging at 1.5/3T (0.21 [95%-CI 0.15-0.29], p < 0.001; 11 publications) (Fig. 4) .

All 17 studies investigating LME in MS employed both a postcontrast 3D T2w-FLAIR and a postcontrast 3D T1w sequence to detect LME. Of note, 1 study acquired 2D scans instead of 3D, showing the lowest LME proportion among all MS studies (<0.01, 1/112 cases) (Eisele et al., 2015) . The acquisition of the 3D T2w-FLAIR sequence was mostly 10 min after Gd-injection, with two studies reporting either earlier (3 min) (Coulette et al., 2019) or later acquisition (up to 54 min) (Titelbaum et al., 2020) . It is noteworthy that latter study suggested that individual LME foci might have different enhancement kinetics and thus different peak enhancement time points, and that differences in LME detection between scanner types could be due to differences in 3D T2w-FLAIR sequences.

In a non-MS cohort, it has been shown that 3D T2w-FLAIR can have higher sensitivity to detect gadolinium enhancement compared to T1w imaging, particularly for superficial enhancement (Mathews et al., 1999) . Along these lines, one MS study found lower sensitivity for LME detection using T1w sequences compared to T2w-FLAIR (Makshakov et al., 2017) . Another study compared LME detection on 3D T2w-FLAIR postcontrast images in native space (method 1), on pre-and postcontrast 3D T2w-FLAIR images in native space (method 2), and on pre-/postcontrast 3D T2w-FLAIR co-registered and subtracted images (method 3) (Zivadinov et al., 2018) . In total, 51 (20%) MS cases showed LME using method 1; 39 (15%) using method 2; and 39 (15%) using method 3. The mean time to analyze the 3D T2w-FLAIR images was lower with method 2 compared to the other 2 methods.

3.3.2.3. LME phenotypes. Overall, two configurations of LME have been described, albeit with inhomogeneous nomenclature: nodular and "spread-fill" (subsuming linear, laminar, and plate-like). Most studies described these two phenotypes (12/17 publications) (Absinta et al., 2017; Absinta et al., 2015; Coulette et al., 2019; Harrison et al., 2017b; Hildesheim et al., 2020; Ighani et al., 2020; Makshakov et al., 2017; Titelbaum et al., 2020; Zivadinov et al., 2017; Zurawski et al., 2020) . 1 early publication with a very low LME proportion of < 0.01 exclusively described a nodular LME phenotype (Eisele et al., 2015) . 5 publications did not report on the LME pattern.

The prevalence of these patterns varied considerably between studies: 4 publications observed higher frequencies of nodular LME: 60% (vs. spread 40%) (Zurawski et al., 2020) , 54% (vs. 13% linear and 31% plate-like) (Makshakov et al., 2017) , 80% (vs. linear and plate-like) (Zivadinov et al., 2017) , and 89% (vs. 11% filling-like) (Hildesheim et al., 2020) . Two publications described higher frequencies of linear/ spread-fill LME: 59-61% for spread-fill sulcal or gyral (vs. nodular) (Ighani et al., 2020) and 76% spread-fill (vs. 15% nodular) (Harrison et al., 2017b) . The latter study observed simultaneous presence of both LME phenotypes in 38% of MS cases.

Eleven studies did not include longitudinal MRI data and did thus not assess temporal evolution of LME. The remaining 6 studies consistently reported mostly stable LME foci over several years. One study with a follow-up period of up to 5.5 years reported that 85% of LME foci remained stable and that only 6 new LME foci were detected over this observation period (in 4 of 299 MS patients) (Absinta et al., 2015) . Similar high percentages of stable LME foci have been observed in other studies: 75% stable over 24 months (and 2 new LME foci in 2/120 patients) , 90% stable over 18 months (and 14 new LME foci) (Hildesheim et al., 2020) , 100% stable over 24 weeks (Bhargava et al., 2019) , and 73-100% stable over 24 months (Jonas et al., 2018) . The latter study also included non-LME enhancement patterns and found that subarachnoid nodular and spread/fill LME patterns persisted less often than dural or vessel wall foci, as well as that MS patients with EDSS progression showed more persistent LME foci.

Three studies found an association between LME and age and/or disease duration (Absinta et al., 2015; Hildesheim et al., 2020; Makshakov et al., 2017) , which was not confirmed for disease duration in 1 study (Zivadinov et al., 2018 ). An association between LME and Expanded Disability Status Scale (EDSS) was described in 3 studies (Absinta et al., 2015; Makshakov et al., 2017; Zivadinov et al., 2018) but was not confirmed in 1 study after adjusting for age (Hildesheim et al., 2020) . MS relapse rate was not associated with LME in 2 studies (Makshakov et al., 2017; Zivadinov et al., 2017) .

Five studies assessed the association between LME and T1 or T2 lesion volume. Three studies found such an association (Zivadinov et al., 2018; Zivadinov et al., 2017; Zurawski et al., 2020) , whereas 2 did not (Harrison et al., 2017b; Hildesheim et al., 2020) . Six studies consistently reported lower cortical gray matter volume and/or thickness in MS cases with LME Harrison et al., 2017b; Ighani et al., 2020; Makshakov et al., 2017; Zivadinov et al., 2017; Zurawski et al., 2020) . Two studies assessed the association of LME with cortical MS lesions at 7 T; one of these studies found no such association (Ighani et al., 2020) while the other did (Zurawski et al., 2020) . Both studies found an association of LME with subcortical gray matter MS lesions (thalamic and hippocampal, respectively).

In view of the inconsistency regarding the association of LME with clinical and imaging parameters in MS, we assessed these effects in a meta-analysis (for all outcomes reported in ≥ 3 publications). In this analysis, the presence of LME was associated with longer disease duration (mean difference 2.2 years [95%-CI 0.2-4.2], p = 0.03, Fig. 5A ) and higher EDSS (mean difference 0.6 EDSS points [95%-CI 0.2-1.0], p = 0.006, Fig. 5B ). Additionally, MS cases with LME showed higher T1 lesion volume (mean difference 1.5 ml [95%-CI 0.1-3.0], p = 0.04, Fig. 5C ), higher T2 lesion volume (mean difference 5.9 ml [95%-CI 3.2-8.6], p < 0.001, Fig. 5D ), and lower cortical volume (mean difference − 21.3 ml [95%-CI − 34.7--7.89], p = 0.002, Fig. 5E ).

One study performed histopathological validation of three LME foci in two progressive MS cases (Absinta et al., 2015) . The gyri adjacent to the LME foci were affected by confluent cortical demyelination and/or subpial cortical demyelination. Leptomeningeal perivascular inflammation, including T cells, B cells, and macrophages, was detected in these areas.

We included two studies that assessed LME in murine EAE using postcontrast T2w-FLAIR. The first study employing 9.4 T MRI found that all 13 inoculated mice showed LME foci, compared to none of the control mice (Pol et al., 2019) . Peak LME intensity was at 10 days post induction and correlated with weight loss and clinical symptoms. In a histopathological analysis, LME foci were associated with high densitiy of Iba-1 positive microglia cells as well as T and B cells, which were absent in control mice. The second study at 11.7 T showed that mice treated with a Bruton tyrosine kinase- Table 1 Synopsis of studies assessing leptomeningeal enhancement (LME) in multiple sclerosis (MS). Nodular, spread/fillsulcal (59%), spread/ fill-gyral (61%), spread/ fill-infratentorial 33/41 MS patients had LME (81%) and 27 had > 1 LME focus. One LME focus was found in 3/5 healthy controls (60%), one subject with a nodular LME and two cases with one spread/fillsulcal LME each. None of the control subjects had >1 LME focus.Association of LME with imaging/clinical parameters:There was an association between spread/fill-sulcal LME and hippocampal lesion count in RRMS. Participants with RRMS had no correlation with cortical lesions, but significant correlations were detected between LME and hippocampal lesion count, normalized cortical gray matter volume, and mean cortical thickness. WM lesion volume was greater in patients with >1 focus of spread/fillsulcal LME compared to those with ⩽1 focus.Temporal dynamics of LME:N/A inhibitor (evobrutinib) had a reduced number of LME foci, while anti-CD20 therapy had no effect on LME (Bhargava et al., 2021) . The pathological tissue substrate showed that this corresponded to a reduction in B cells within regions of meningeal inflammation as well as reduced astrocytosis in the adjacent cortex. Interestingly, myeloid cell infiltrates seemed to persist despite B cell depletion.

Four studies assessed the impact of drug treatment on LME resolution. One study found similar LME persistence rates in MS patients with/without disease-modifying therapy (DMT) (Jonas et al., 2018) . Another study assessing the efficacy of dimethyl fumarate or teriflunomide on LME reported no differences in LME resolution between treatment groups (8 of 12 patients showed stable LME, and 2 patients developed new LME) . One study assessing intrathecal rituximab treatment in 15 progressive MS patients observed stable LME foci in all patients over the 24-week follow-up period (Bhargava et al., 2019) . In contrast to these studies with relatively small sample size and consequently lower statistical power, one study including 241 MS patients observed resolution of LME in 2 patients after high-dose steroid treatment within 6 months followup (Titelbaum et al., 2020) . Studies are in chronological and alphabetical order. Abbreviations: FLAIR, fluid-attenuated inversion recovery (MP, magnetization-prepared); HC, healthy control; LME, leptomeningeal enhancement; MS, multiple sclerosis (RR relapsing-remitting, SP, secondary progressive; PP, primary progressive); pc, post-contrast. 3.4.1.2. LME pattern. 32 studies did not report on the LME pattern, while 4 studies did (2 spread, 2 nodular). 33 studies did not report on the LME evolution over follow-up, while 3 studies reported LME increase with clinical worsening, and 1 study in cryptococcal meningitis reported LME resolution with clinical improvement (Sarkis et al., 2015) .

Most studies employed a postcontrast T1w sequence to visualize LME (21 publications), followed by T2w-FLAIR (7 publications). 6 studies did not report which sequences were used for LME detection.

A meta-analysis on LME in infectious diseases, including a total of 831 cases, showed an overall proportion of 0.59 [95%-CI: 0.47-0.69] with substantial heterogeneity across studies (I 2 = 86%, p < 0.01) (Fig. 6 ). COVID-19 had the lowest proportion of LME with 0.24 [95%-CI 0.13-0.41].

Studies reporting on LME in neoplastic CNS diseases were associated with primary CNS tumors (92 publications: CNS lymphoma, choroid plexus papilloma, meningioma, germinoma, lipoma, primitive neuroectodermal tumors (PNET), diffuse leptomeningeal glioneuronal tumor, midline glioma, hemangioblastoma, glioblastoma/high-grade astrocytoma, Hodgkin lymphoma, xanthogranuloma, medulloblastoma, melanoma, oligodendroglioma, pilocytic astrocytoma, anaplastic astrocytoma, and giant cell astrocytoma), leptomeningeal metastases (47 publications: metastases from breast cancer, acute myeloid leukemia, rhabdomyosarcoma, gastric cancer, lung adenocarcinoma, smallcell lung cancer, pancreatic cancer, melanoma, Waldenstrom macroglobulinemia [Bing-Neel syndrome], and multiple myeloma), and hereditary tumor syndromes (5 publications: von Hippel-Lindau syndrome, Klippel-Trenaunay-Weber syndrome, and tuberous sclerosis).

28 studies did not report on the LME pattern, while 8 studies did (3 spread, 3 nodular, 2 laminar/linear). 33 studies did not report on LME evolution over follow-up, while 1 study in glioblastoma reported persistent LME at follow-up MRI (up to two years later). (Kim et al., 2018) 

Most studies employed a postcontrast T1w sequence to visualize LME (23 publications) followed by a postcontrast T2w-FLAIR (6 publications). 9 studies did not report which sequences were used for LME detection. Fig. 4 . Forest plot of leptomeningeal enhancement (LME) proportions in multiple sclerosis (MS) with B 0 magnetic field strength as moderator. Pooled analyses of studies comparing the proportion of LME on MRI in MS, stratified by magnetic field strength. Proportions for LME were extracted and pooled using the random effects DerSimonian-Laird method. Abbreviations: CI confidence interval.

A meta-analysis on LME in neoplastic diseases, including a total of 1393 cases, showed an overall proportion of 0.47 [95%-CI: 0.37-0.57] with substantial heterogeneity across studies (I 2 = 90%, p < 0.01) (Fig. 7) . CNS leukemia had the lowest proportion of LME with 0. Fig. 6 . Forest plot of leptomeningeal enhancement (LME) proportions in infectious neurological diseases. Pooled analyses of studies comparing the proportion of LME on MRI in infectious neurological diseases. Static magnetic field strength for MRI acquisition for respective studies are listed in brackets if reported. Proportions for LME were extracted and pooled using the random effects DerSimonian-Laird method. Abbreviations: CI confidence interval.

Of 147 publications, the most notable neurological diseases not belonging to the classes above were: rheumatoid arthritis with meningitis (16 publications), Sturge-Weber syndrome (16 publications), familial leptomeningeal amyloidosis/polyneuropathy (11 publications), ischemic (reversible cerebral vasoconstriction syndrome, stroke, post interventional revascularization, severe carotid stenosis, 11 publications), cerebral amyloid angiopathy (7 publications), epileptic seizures (6 publications), Moyamoya disease (6 publications), intoxications/ drug-induced LME (abrin, ibuprofen, ipilimumab, propofol [in children] , tacrolimus; 5 publications), hemophagocytic lymphohistiocytosis (4 publications), posterior reversible encephalopathy syndrome (PRES) (4 publications), Rosai-Dorfman disease (3 publications), hepatic encephalopathy (3 publications), Sjogren syndrome (2 publications), and traumatic brain injury (2 publications).

A meta-analysis on diseases with ≥ 2 publications and ≥ 10 subjects per study, including a total of 187 cases, showed an LME proportion of 0.31 [95%-CI 0.16-0.52] in cerebral amyloid angiopathy and 0.69 [95%-CI 0.27-0.93] in reversible cerebral vasoconstriction syndrome (Fig. 8A) . (Itsekson Hayosh et al., 2020; Wu et al., 2021) 3.7. Leptomeningeal enhancement in healthy controls LME has also been reported in healthy subjects (6 publications). A meta-analysis of 4 publications, including a total of 163 individuals, corroborated the presence of LME in this group, albeit at a low overall proportion of around 0.06 [95%-CI 0.03-0.11] (Fig. 8B ). In addition to the low proportions of LME, it has been shown in 2 publications that none of the LME-positive control subjects had more than 1 LME focus. (Ighani et al., 2020; Zurawski et al., 2020) In another publication, the 2 LME-positive controls exclusively presented with more than one nodular Fig. 7 . Forest plot of leptomeningeal enhancement (LME) proportions in neoplastic neurological diseases. Pooled analyses of studies comparing the proportion of LME on MRI in infectious neurological diseases. Static magnetic field strength for MRI acquisition for respective studies are listed in brackets if reported. Proportions for LME were extracted and pooled using the random effects DerSimonian-Laird method. Abbreviations: CI confidence interval; CNS, central nervous system. LME foci. (Harrison et al., 2017a) 4. Discussion

This study aims to provide systematic evidence on LME proportion in neurological diseases, including MS, and to determine whether the role of LME as a prognostic biomarker for MS is substantiated in the literature. Overall, primary neuroinflammatory diseases showed lower LME proportion (0.26 [95%-CI: 0.20-0.35]) compared to neoplastic (0.47 [95%-CI: 0.37-0.57]) or infectious neurological diseases (0.59 [95%-CI: 0.47-0.69]). Additionally, the presence of LME was associated with worse clinical and imaging parameters in MS, that is, on average MS patients with LME had 2 years longer disease duration (p = 0.03), higher EDSS by 0.7 points (p = 0.006), 21 ml less cortical volume (p = 0.002), 5.9 ml more T2 lesion volume (p < 0.001), and 1.6 ml more T1 lesion volume (p = 0.04) compared to MS patients without LME. Finally, based on a few histopathological validation studies in MS and neuroinflammatory animal models, LME corresponds to meningeal inflammatory infiltrates as well as microglial activation in the adjacent cortex. However, the evidence supporting the association of LME with cortical MS pathology remains conflicting.

A wide variety of disorders may present with LME, including neoplastic and infectious neurological diseases, making LME a highly nonspecific imaging finding. However, proportions of LME have considerable ranges across different neurological diseases. High LME proportions (on the order of 0.75), have been observed in Bing-Neel syndrome (a rare complication of Waldenstrom's macroglobulinemia) (Castillo et al., 2015; Itchaki et al., 2018) and infectious meningitis (Ahmad et al., 2015; Kralik et al., 2019; Soni et al., 2020) . Interestingly, a subset of smaller studies employing ultrahigh-field (7 T) static magnetic field strengths also found proportions of LME around 0.8 in MS (Harrison et al., 2017b; Ighani et al., 2020; Zurawski et al., 2020) , which may indicate a need for higher static magnetic field strengths to facilitate LME detection.

Other notable diseases with LME include ischemic neurological diseases, such as reversible cerebral vasoconstriction syndrome (proportion around 0.7) (Itsekson Hayosh et al., 2020; Wu et al., 2021) and stroke (not included in the meta-analysis) (Henning et al., 2008; Latour et al., 2004; Warach and Latour, 2004) . The presence of LME in brain ischemia also suggests a relevant role of the leptomeningeal compartment in its pathogenesis. Here, LME on post-contrast T2w-FLAIR has been attributed to early blood-brain-barrier disruption , also being associated with hemorrhagic transformation and worse clinical outcomes . Furthermore, poor leptomeningeal collateral flow has been associated with worse clinical outcome in acute stroke (Menon et al., 2013) . Finally, also COVID-19 has been reported to present with LME, albeit with low proportions around 0.25 (Klironomos et al., 2020; Kremer et al., 2020; Lersy et al., 2020) .

Several primary neuroinflammatory diseases can also present with LME, among them neurosarcoidosis (proportion around 0.4), MS (0.3), primary angiitis of the CNS (0.2), NMOSD (0.06), and Susac's syndrome (not included in the meta-analysis) (Susac et al., 2003) . Of note, in MS, LME proportions seem to vary among clinical phenotypes, with relapsing-remitting having lower proportions than progressive MS (0.2 vs. 0.4). However, overall longer disease duration in progressive MS could be a confounding factor.

Our meta-analysis substantiates the role of LME as prognostic biomarker in MS. The presence of LME was associated with worse physical disability and higher lesion burden as well as lower cortical volumesthe latter being also associated with worse clinical MS outcomes (reviewed in (Calabrese et al., 2015) ). With this, our study highlights the relevance of including LME in routine clinical imaging. Along these lines, ultrahigh-field imaging at 7 T might substantially improve the sensitivity to detect LME in MS in the clinical setting, as shown by our meta-analysis.

One major remaining question about LME is its underlying tissue signature. In neoplastic and infectious CNS diseases, LME likely corresponds to increased local blood supply and/or extravasation of gadolinium. However, in neuroinflammatory diseases, the pathological substrate of LME is much less clear. Based on limited EAE and MS histopathology data, LME corresponds to meningeal inflammatory infiltrates and/or tertiary lymphoid follicles (reviewed in (Zurawski et al., 2017) ) (Absinta et al., 2015; Bhargava et al., 2021) . Despite conflicting evidence as to whether LME is spatially associated with cortical pathology in MS (Absinta and Ontaneda, 2020) , there has been a consistent association of LME with low cortical volumes across studies, also substantiated by our meta-analysis. This indicates that the pathology underlying L ME could exert a diffusely deleterious effect on cortical gray matter.

Different LME patterns have been described in MS (Harrison et al., 2017a ) and, to a much lesser extent, in other neuroinflammatory diseases such as Susac syndrome (Coulette et al., 2019) , neurosarcoidosis (Junger et al., 1993; O'Connell et al., 2017) , and NMOSD (Asgari et al., 2017; Fan et al., 2016; long et al., 2014) . LME patterns were very rarely reported in non-inflammatory neurological diseases, mostly as diffuse LME in neoplastic neurological diseases (Schluterman et al., 2004) . In MS, the prevalence of different LME patterns, their nomenclature as well as their association to clinical measures were highly inconsistent among studies. Nevertheless, different LME patterns could represent distinct pathophysiological features, also emphasized by the observation that healthy controls may present with nodular but not non-nodular LME (Harrison et al., 2017a) . With this, more data and a more stringent nomenclature is needed to describe LME phenotypes and their potential association to clinical disability and disease phenotypes. We favor the nomenclature convention of nodular versus linear LME.

It is interesting that LME has also been observed in healthy controls, albeit at low proportions (0.06) (Absinta et al., 2017; Absinta et al., 2015; Sommer et al., 2020; Zurawski et al., 2020) . The etiology of LME foci in healthy subjects is still a matter of debate. However, one potential cause could be minor traumatic brain injuries. It should be emphasized that LME foci can be very subtle and can easily be misinterpreted on MRI. Hence, several imaging pitfalls for LME should be taken into account, among them: gadolinium leakage of indeterminate biological significance, enhancement related to slow blood flow of cortical veins, or anatomic structures as well as imaging artifacts (Titelbaum et al., 2020) .

Finally, data from clinical studies do not suggest a therapeutic effect of DMTs on LME in MS. However, most of these studies have a small sample size and might thus be insufficiently powered to detect a potential therapeutic effect. In addition, newer DMTs such as Bruton tyrosine kinase inhibitors (Sellebjerg and Weber, 2021) have not been assessed in this regard, even though these drugs led to a resolution of LME in one rodent study employing a neuroinflammatory model (Bhargava et al., 2021) . Hence, more data is needed on potential therapeutic impact of DMT on LME resolution.

Our study has some limitations: First, a wide variety of imaging methods have been employed to detect LME, for which we only partially corrected our analysis (e.g., static magnetic field strengths). Notably, the use of either T1w or T2w-FLAIR postcontrast sequences was not considered, with the latter generally having higher sensitivity to detect LME (Makshakov et al., 2017; Singh et al., 2000) . This could have led to an underestimation of LME proportions in studies acquiring T1w sequences. However, studies in neoplastic and infectious neurological diseases with mostly bulk LME mainly employed T1w sequences, potentially counterbalancing this effect. Along these lines, we also point out that a substantial number of studies did not report on which MRI sequences they employed (T1w versus T2w-FLAIR) and only scant additional data were obtainable by directly contacting study authors. Second, for assessing the prognostic value of LME, we pooled studies with various methodological backgrounds for summary estimates. Nonetheless, the outcome measures reported were surprisingly uniform, even allowing for the use of mean differences in our meta-analysis.

Our study provides systematic evidence for LME proportions in a comprehensive panel of neurological diseases, including MS. This highlevel evidence also corroborates the prognostic value of LME in MS. With this, LME qualifies to be included as a standard imaging feature in clinical MS imaging in our opinion, not least to enhance the knowledge and experience of radiologists and referring neurologists on this matter (Okar and Reich, 2021) . Furthermore, our systematic review identified several methodological factors which need to be considered when assessing LME, including technical parameters such as magnetic field strength, type of 3D T2w-FLAIR sequence, and scanner type but also timing of acquisition as well as exclusion of LME imaging mimicks (Titelbaum et al., 2020) . We also identified knowledge gaps: First, more data is needed on the potential therapeutic impact on LME in MS. Second, more evidence on the pathological substrate of LME and on its potential association with cortical pathology in neuroinflammation is warranted to further improve our understanding for this MRI feature and to strengthen its role in the clinical and research settings.

Our systematic review and meta-analysis synthesize leptomeningeal enhancement proportions across a comprehensive panel of neurological diseases, including multiple sclerosis, and assesses its prognostic value in multiple sclerosis.

•Leptomeningeal enhancement (LME) is a nonspecific imaging feature present across many neurological disorders, including neoplasm, infection, and primary neuroinflammation.

•The presence of LME is associated with worse clinical and imaging outcomes in multiple sclerosis, justifying its ascertainment in clinical practice.

•Neuroinflammatory animal models can be used to further investigate the pathophysiology of LME, including its pathological tissue signature and/or its association with cortical pathology.

BVI was supported by the Forschungskredit from the University of Zurich. CT was supported by the Swiss National Science Foundation (Grant number: 320030_156860), the Stiftung zur Förderung der gastroenterologischen und allgemeinen klinischen Forschung, as well as from the University of Basel (Grant numbers: 3MS1020 and 3MS1049). MA is supported by the Conrad N. Hilton Foundation (Marylin Hilton Bridging Award for Physician-Scientists, grant #17313), the Roche Foundation for Independent Research, the Cariplo Foundation (grant #1677) and the FRRB Early Career Award (grant #1750327). The study was partially supported by the Intramural Research Program of NINDS, NIH. 

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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We thank Irene Cortese, Govind Nair, Avindra Nath, and Bryan Smith for facilitating MRI acquisition. We also thank the Intramural Research Program of National Institute of Neurological Disorders and Stroke for financial support.

Supplementary data to this article can be found online at https://doi. org/10.1016/j.nicl.2022.102939.