NCMP-03. ANATOMIC AND SURGICAL FACTORS PREDICT DEVELOPMENT OF LEPTOMENINGEAL DISEASE IN PATIENTS WITH METASTATIC MELANOMA

Leptomeningeal disease (LMD) is a devastating complication of systemic malignancy, portending a poor prognosis with an estimated median survival of 4-6 weeks if left untreated. Several reports have suggested surgical resection as a potential causative factor. Herein, we explore if surgical and anatomical factors are correlated with development of LMD in patients with melanoma brain metastases. METHODS: Patients treated at our institution between 1999-2019 for primary melanoma with brain metastasis were compiled into a database based on ICD9/10 coding. 1,079 patients with melanoma brain metastases and appropriate imaging were identified, and 834 patients with a minimum of 3 months’ follow up were included. Patients were dichotomized by development of LMD or lack thereof, and categorized into an overall cohort, and surgical and non-surgical cohorts. Anatomic factors and ventricular access during surgery were investigated as possible correlative factors for the development of LMD. RESULTS: In the overall cohort, female gender(p=0.033), presence of dural metastasis(p=0.018), presence of periventricular lesions(p< .001), presence of intraventricular lesions(p< .001), and ventricular access during surgery(p< .001) were significantly associated with LMD. Patients undergoing surgery, or those undergoing surgery without ventricular access, were not at higher risk of LMD. On multivariate analysis, female gender(p=.033), presence of periventricular lesions (p< .001), presence of intraventricular lesions(p< .002), and presence of dural metastasis(p=0.032) were significantly associated with development of LMD. In patients who had surgery, iatrogenic ventricular access(p< .001) was significantly correlated with LMD. In the group of patients without surgery, those with periventricular lesions had significantly higher odds of LMD(p< .001). CONCLUSIONS: In a retrospective cohort of patients with melanoma metastatic to the brain, surgical intervention does not increase odds of LMD; however, iatrogenic access to the CSF space during surgery is highly correlated with LMD development. Anatomic contact with the CSF space predicts LMD regardless of surgical status.

Performance of the 2017 and 2010 Revised McDonald Criteria in Predicting MS Diagnosis After a Clinically Isolated Syndrome

Background and ObjectivesTo compare the performance of the 2017 revisions to the McDonald criteria with the 2010 McDonald criteria in establishing MS diagnosis and predicting prognosis in patients with clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS).MethodsCSF examination, brain and spinal cord MRI obtained ≤5 months from CIS onset, and a follow-up brain MRI acquired within 15 months from CIS onset were evaluated in 785 CIS patients from 9 European centers. Date of second clinical attack and of reaching Expanded Disability Status Score (EDSS) ≥ 3.0, if they occurred, were also collected. Performance of the 2017 and 2010 McDonald criteria for dissemination in space (DIS), time (DIT) (including oligoclonal bands assessment) and DIS + DIT for predicting a second clinical attack (clinically definite [CD] MS) and EDSS ≥ 3.0 at follow-up was evaluated. Time to MS diagnosis for the different criteria was also estimated.ResultsAt follow-up (median = 69.1 months), 406/785 CIS patients developed CDMS. At 36 months, the 2017 DIS + DIT criteria had higher sensitivity (0.83 vs 0.66), lower specificity (0.39 vs 0.60) and similar area under the curve values (0.61 vs 0.63). Median time to MS diagnosis was shorter with the 2017 vs the 2010 or CDMS criteria (2017 revision = 3.2; 2010 revision = 13.0; CDMS = 58.5 months). The 2 sets of criteria similarly predicted EDSS ≥ 3.0 milestone. Three periventricular lesions improved specificity in patients ≥45 years.DiscussionThe 2017 McDonald criteria showed higher sensitivity, lower specificity and similar accuracy in predicting CDMS compared to 2010 McDonald criteria, while shortening time to diagnosis of MS.Classification of EvidenceThis study provides Class II evidence that the 2017 McDonald Criteria more accurately distinguish CDMS in patients early after a CIS when compared to the 2010 McDonald criteria.

LMD-19. Anatomic and Surgical Factors Predict Development of Leptomeningeal Disease in Patients with Metastatic Melanoma

Background Leptomeningeal disease (LMD) is a devastating complication of systemic malignancy, portending a poor prognosis with an estimated median survival of 4–6 weeks if left untreated. Several reports have suggested surgical resection, particularly piecemeal resection, as a potential causative factor. Herein, we explore if surgical and anatomical factors are correlated with development of LMD in patients with melanoma brain metastases. Methods Patients treated at our institution between 1999–2019 for primary melanoma with brain metastasis were compiled into a database based on ICD9/10 coding. 1,079 patients with melanoma brain metastases and appropriate imaging were identified, and 834 patients with a minimum of 3 months’ follow up were included. Patients were dichotomized by development of LMD or lack thereof. General demographic information, surgical and anatomic data, and ventricular access during surgery were investigated as possible correlative factors for the development of LMD. Results On univariate analysis, female gender (p=0.033), presence of dural metastasis (p=0.018), presence of periventricular lesions (p<.001), presence of intraventricular lesions (p<.001), and ventricular access during surgery (p<.001) were significantly associated with LMD. Patients undergoing surgery, or those undergoing surgery without ventricular access, were not at higher risk of LMD. Administration of immunotherapy, either as first-line or salvage therapy, did not impact rates of LMD. On multivariate analysis, female gender (p=.033), presence of periventricular lesions (p<.001), presence of intraventricular lesions (p<.002), and presence of dural metastasis (p=0.032) were significantly associated with development of LMD. In patients who had surgery, iatrogenic ventricular access (p<.001) was significantly correlated with LMD. Conclusions In a retrospective cohort of patients with melanoma metastatic to the brain, those patients with pre-existing lesions in contact with the CSF space are more likely to develop LMD than those who do not. In addition, iatrogenic access to the CSF space during surgery is highly correlated with LMD development.

Transcriptomic Analysis of Age-Associated Periventricular Lesions Reveals Dysregulation of the Immune Response

White matter lesions (WML) are a common feature of the ageing brain associated with cognitive impairment. The gene expression profiles of periventricular lesions (PVL, n = 7) and radiologically-normal-appearing (control) periventricular white matter cases (n = 11) obtained from the Cognitive Function and Ageing Study (CFAS) neuropathology cohort were interrogated using microarray analysis and NanoString to identify novel mechanisms potentially underlying their formation. Histological characterisation of control white matter cases identified a subgroup (n = 4) which contained high levels of MHC-II immunoreactive microglia, and were classified as “pre-lesional.” Microarray analysis identified 2256 significantly differentially-expressed genes (p ≤ 0.05, FC ≥ 1.2) in PVL compared to non-lesional control white matter (1378 upregulated and 878 downregulated); 2649 significantly differentially-expressed genes in “pre-lesional” cases compared to PVL (1390 upregulated and 1259 downregulated); and 2398 significantly differentially-expressed genes in “pre-lesional” versus non-lesional control cases (1527 upregulated and 871 downregulated). Whilst histological evaluation of a single marker (MHC-II) implicates immune-activated microglia in lesion pathology, transcriptomic analysis indicates significant downregulation of a number of activated microglial markers and suggests established PVL are part of a continuous spectrum of white matter injury. The gene expression profile of “pre-lesional” periventricular white matter suggests upregulation of several signalling pathways may be a neuroprotective response to prevent the pathogenesis of PVL.

Evaluation of brain and spinal cord lesion distribution criteria at disease onset in distinguishing NMOSD from MS and MOG antibody-associated disorder

Objective: To validate the recently proposed imaging criteria in distinguishing aquaporin-4 antibody (AQP4-ab)-seropositive neuromyelitis optica spectrum disorder (NMOSD) from multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein antibody-associated disorder (MOG-AD) at disease onset in a Chinese population. Methods: We enrolled 241 patients in this retrospective study, including 143 AQP4-ab-seropositive NMOSD, 73 MS, and 25 MOG-AD. Cacciaguerra’s criteria were described as fulfillment of at least 2/5 conditions including the absence of the combined juxtacortical/cortical lesions, the presence of longitudinal extensive transverse myelitis (LETM) lesions, the presence of periependymal-lateral ventricles lesions, the absence of Dawson’s fingers lesions, and the absence of periventricular lesions. Results: Fulfillment of at least 3/5 conditions was able to differentiate NMOSD from MS with a good diagnostic performance (accuracy = 0.92, sensitivity = 0.91, specificity = 0.93), yet failed to differentiate NMOSD from MOG-AD. LETM lesions showed the highest accuracy (0.78), sensitivity (0.70), and specificity (0.97) for NMSOD. Conclusion: Our research suggested the utility of Cacciaguerra’s criteria in a Chinese population at disease onset. A better diagnostic performance in NMOSD could be attained with at least 3/5 conditions fulfilled. Yet their utility in distinguishing NMOSD from MOG-AD was limited.

In vivo microstructural heterogeneity of white matter lesions in Alzheimer’s disease using tissue compositional analysis of diffusion MRI data

White matter hyperintensities (WMH) are commonly observed in elderly individuals, and are typically more prevalent in Alzheimer’s disease subjects than in healthy subjects. These lesions can be identified on fluid attenuated inversion recovery (FLAIR) MRI, on which they are hyperintense compared to their surroundings. These MRI-visible lesions appear homogeneously hyperintense despite known heterogeneity in their pathological underpinnings, and are commonly regarded as surrogate markers of small vessel disease in in vivo studies. Consequently, the extent to which these lesions contribute to Alzheimer’s disease remains unclear, likely due to the somewhat limited way in which these lesions are assessed in vivo. Diffusion MRI is sensitive to white matter microstructure, and might thus be used to investigate microstructural changes within WMH. In this study, we applied a method called single-shell 3-tissue constrained spherical deconvolution, which models white matter microstructure while also accounting for other tissue compartments, to investigate WMH in vivo. Diffusion MRI data and FLAIR images were obtained from Alzheimer’s disease (n = 48) and healthy elderly control (n = 94) subjects from the Australian Imaging, Biomarkers and Lifestyle study of ageing. WMH were automatically segmented and classified as periventricular or deep lesions from FLAIR images based on their continuity with the lateral ventricles, and the 3-tissue profile of different classes of WMH was characterised by three metrics, which together characterised the relative tissue profile in terms of the white matter-, grey matter-, and fluid-like characteristics of the diffusion signal. Our findings revealed that periventricular and deep lesion classes could be distinguished from one another, and from normal-appearing white matter based on their 3-tissue profile, with substantially higher free water content in periventricular lesions than deep. Given the higher lesion load of periventricular lesions in Alzheimer’s disease patients, the 3-tissue profile of these WMH could be interpreted as reflecting the more deleterious pathological underpinnings that are associated with disease. However, when alternatively classifying lesion sub-regions in terms of distance contours from the ventricles to account for potential heterogeneity within confluent lesions, we found that the highest fluid content was present in lesion areas most proximal to the ventricles, which were common to both Alzheimer’s disease subjects and healthy controls. We argue that whatever classification scheme is used when investigating WMH, failure to account for heterogeneity within lesions may result in classification-scheme dependent conclusions. Future studies of WMH in Alzheimer’s Disease would benefit from inclusion of microstructural information when characterising lesions.

How much do periventricular lesions assist in distinguishing migraine with aura from CIS?

ObjectiveTo evaluate in clinically isolated syndrome (CIS) and migraine with aura (MA) how the number of periventricular lesions (PVLs) detected at MRI influences diagnostic performance when the Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) or the 2017 revised criteria are applied.MethodsIn this retrospective study, white matter hyperintensities (WMH) of 84 patients with MA and 79 patients with CIS were assessed using manual segmentation technique. Lesion probability maps (LPMs) and voxel-wise analysis of lesion distribution by diagnosis were obtained. Furthermore, we performed a logistic regression analysis based on lesion locations and volumes.ResultsCompared to patients with MA, patients with CIS showed a significant overall higher T2 WMH mean number and volume (17.9 ± 16.9 vs 6.2 ± 11.9 and 3.1 ± 4.2 vs 0.3 ± 0.6 mL; p < 0.0001) and a significantly higher T2 WMH mean number in infratentorial, periventricular, and juxtacortical areas (p < 0.0001). LPMs identified the periventricular regions as the sites with the highest probability of detecting T2 WMH in patients with CIS. Voxel-wise analysis of lesion distribution by diagnosis revealed a statistically significant association exclusively between the diagnosis of CIS and the PVLs. MAGNIMS criteria demonstrated the highest specificity in differentiating patients with CIS from patients with MA (100% vs 87%) against a predictable lower sensitivity (63% vs 72%).ConclusionsPVLs play a key role in the differential diagnosis between MA and CIS, particularly when there are more than 3. Future studies on multiple sclerosis criteria might reconsider the 3 PVLs to minimize the risk of misdiagnosis.Classification of evidenceThis study provides Class IV evidence that the presence at least 3 PVLs increases the specificity in distinguishing MA from CIS.

Lesion topographies in multiple sclerosis diagnosis

Objectives:To assess the contributions of cortico-juxtacortical and corpus callosum lesions to multiple sclerosis diagnosis and to compare the value of ≥1 vs ≥3 periventricular lesions in clinically isolated syndromes (CIS).Methods:Step 1: We evaluated lesion topography classifications in 657 patients with CIS with stepwise Cox proportional hazards regression models considering second attack as the outcome. Step 2: We established 2 dissemination in space (DIS) versions according to the periventricular lesion cutoffs of ≥1 and ≥3 and assessed their performance at 10 years with second attack as the outcome, first individually and then combined with dissemination in time (DIT) in all cases (n = 326), by age, and by CIS topography.Results:Step 1: The models (hazard ratios [95% confidence interval]) favored ≥1 over ≥3 periventricular lesions (2.5 [1.7–3.6]) and cortico-juxtacortical over juxtacortical lesions (1.4 [1.0–1.8]). Callosal lesions were not selected. Step 2: DIS specificity with ≥1 periventricular lesions was slightly lower than with ≥3 (59.1 vs 61.4) and the same after adding DIT (88.6). Regarding age, ≥3 periventricular lesions improved DIS specificity over ≥1 lesions in the 40–49 years of age bracket (66.7 vs 58.3). This difference disappeared when adding DIT (83.3). Optic neuritis had a similar pattern when evaluating CIS topographies.Conclusions:Our results comply with the Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) consensus recommendation of combining cortical and juxtacortical lesions into a single term when possible. Concerning periventricular lesions, maintaining the current ≥1 cutoff in the McDonald criteria does not compromise specificity in typical CIS cases, but attention should be paid to older patients or optic neuritis cases.