Radiological Features of Herpetic Encephalitis in Children.

BACKGROUND: Nonspecific clinical manifestations and unclear radiological features may delay treatment initiation in pediatric patients with Herpes simplex encephalitis (HSE). The aim of this study is to analyze the clinical and radiological features of the disease. METHODS: Clinical, laboratory, and magnetic resonance imaging (MRI) data were obtained retrospectively from a group of 37 hospitalized pediatric patients older than two months and with a polymerase chain reaction-confirmed HSE diagnosis. Clinical severity (i.e., mechanical ventilatory support) and outcome at discharge (i.e., pediatric modified Rankin Scale [ped-mRS]) were also assessed. RESULTS: Median age was 14 months (interquartile range: 10-36). All patients survived, 15 (41%) had complete recovery (i.e., ped-mRS = 0), and 10 (27%) had significant residual disability at discharge (i.e., ped-mRS ≥3). Brain MRI was obtained in 31 patients. T2-hyperintense lesions were usually bilateral (28, 90%) and multifocal (30, 97%). Hemorrhage and mass effect were observed in 13 (42%) and 15 (48%) patients, respectively. Parenchymal lesions involved the temporal lobes (94%), insula (90%), parietal lobes (84%), and frontal lobes (61%). Occipital lesions were rare. In multivariable binary logistic regression models the presence of altered consciousness was associated with mechanical ventilation (odds ratio [OR] = 8.2, Nagelkerke R2 = 0.22), whereas the involvement of the occipital lobes (OR = 7.8) and the administration of vasopressors (OR = 12.1) were independent predictors of poor outcome (Nagelkerke R2 = 0.41). CONCLUSIONS: Brain MRI is useful for diagnosis and outcome assessment in pediatric HSE. Radiological patterns with common frontotemporal involvement overlap adults, but multifocal and parietal lobe abnormalities are observed as well.

Grey Matter Atrophy and its Relationship with White Matter Lesions in Patients with Myelin Oligodendrocyte Glycoprotein Antibody-associated Disease, Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder, and Multiple Sclerosis.

OBJECTIVE: To evaluate: (1) the distribution of gray matter (GM) atrophy in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD), and relapsing-remitting multiple sclerosis (RRMS); and (2) the relationship between GM volumes and white matter lesions in various brain regions within each disease. METHODS: A retrospective, multicenter analysis of magnetic resonance imaging data included patients with MOGAD/AQP4+NMOSD/RRMS in non-acute disease stage. Voxel-wise analyses and general linear models were used to evaluate the relevance of regional GM atrophy. For significant results (p < 0.05), volumes of atrophic areas are reported. RESULTS: We studied 135 MOGAD patients, 135 AQP4+NMOSD, 175 RRMS, and 144 healthy controls (HC). Compared with HC, MOGAD showed lower GM volumes in the temporal lobes, deep GM, insula, and cingulate cortex (75.79 cm3); AQP4+NMOSD in the occipital cortex (32.83 cm3); and RRMS diffusely in the GM (260.61 cm3). MOGAD showed more pronounced temporal cortex atrophy than RRMS (6.71 cm3), whereas AQP4+NMOSD displayed greater occipital cortex atrophy than RRMS (19.82 cm3). RRMS demonstrated more pronounced deep GM atrophy in comparison with MOGAD (27.90 cm3) and AQP4+NMOSD (47.04 cm3). In MOGAD, higher periventricular and cortical/juxtacortical lesions were linked to reduced temporal cortex, deep GM, and insula volumes. In RRMS, the diffuse GM atrophy was associated with lesions in all locations. AQP4+NMOSD showed no lesion/GM volume correlation. INTERPRETATION: GM atrophy is more widespread in RRMS compared with the other two conditions. MOGAD primarily affects the temporal cortex, whereas AQP4+NMOSD mainly involves the occipital cortex. In MOGAD and RRMS, lesion-related tract degeneration is associated with atrophy, but this link is absent in AQP4+NMOSD. ANN NEUROL 2024;96:276-288.

Radiologic Lag and Brain MRI Lesion Dynamics During Attacks in MOG Antibody-Associated Disease.

BACKGROUND AND OBJECTIVES: Knowledge of the evolution of CNS demyelinating lesions within attacks could assist diagnosis. We evaluated intra-attack lesion dynamics in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) vs multiple sclerosis (MS) and aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorder (AQP4+NMOSD). METHODS: This retrospective observational multicenter study included consecutive patients from Mayo Clinic (USA) and Great Ormond Street Hospital for Children (UK). Inclusion criteria were as follows: (1) MOGAD, MS, or AQP4+NMOSD diagnosis; (2) availability of ≥2 brain MRIs (within 30 days of attack onset); and (3) brain involvement (i.e., ≥1 T2 lesion) on ≥1 brain MRI. The initial and subsequent brain MRIs within a single attack were evaluated for the following: new T2 lesions(s); resolved T2 lesion(s); both; or no change. This was compared between MOGAD, MS, and AQP4+NMOSD attacks. We used the Mann-Whitney U test and χ2/Fisher exact test for statistical analysis. RESULTS: Our cohort included 55 patients with MOGAD (median age, 14 years; interquartile range [IQR] 5-34; female sex, 29 [53%]) for a total of 58 attacks. The comparison groups included 38 patients with MS, and 19 with AQP4+NMOSD. In MOGAD, the initial brain MRI (median of 5 days from onset [IQR 3-9]) was normal in 6/58 (10%) attacks despite cerebral symptoms (i.e., radiologic lag). The commonest reason for repeat MRI was clinical worsening or no improvement (33/56 [59%] attacks with details available). When compared with the first MRI, the second intra-attack MRI (median of 8 days from initial scan [IQR 5-13]) showed the following: new T2 lesion(s) 27/58 (47%); stability 24/58 (41%); resolution of T2 lesion(s) 4/58 (7%); or both new and resolved T2 lesions 3/58 (5%). Findings were similar between children and adults. Steroid treatment was associated with resolution of ≥1 T2 lesion (6/28 [21%] vs 1/30 [3%], p = 0.048) and reduced the likelihood of new T2 lesions (9/28 vs 18/30, p = 0.03). Intra-attack MRI changes favored MOGAD (34/58 [59%]) over MS (10/38 [26%], p = 0.002) and AQP4+NMOSD (4/19 [21%], p = 0.007). Resolution of ≥1 T2 lesions was exclusive to MOGAD (7/58 [12%]). DISCUSSION: Radiologic lag is common within MOGAD attacks. Dynamic imaging with frequent appearance and occasional disappearance of lesions within a single attack suggest MOGAD diagnosis over MS and AQP4+NMOSD. These findings have implications for clinical practice, clinical trial attack adjudication, and understanding of MOGAD pathogenesis.

Diagnostic Utility of MOG Antibody Testing in Cerebrospinal Fluid.

OBJECTIVE: The aim of this study was to assess the diagnostic utility of cerebrospinal fluid (CSF) myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) testing. METHODS: We retrospectively identified patients for CSF MOG-IgG testing from January 1, 1996, to May 1, 2023, at Mayo Clinic and other medical centers that sent CSF MOG-IgG for testing including: controls, 282; serum MOG-IgG positive MOG antibody-associated disease (MOGAD), 74; serum MOG-IgG negative high-risk phenotypes, 73; serum false positive MOG-IgG with alternative diagnoses, 18. A live cell-based assay assessed CSF MOG-IgG positivity (IgG-binding-index [IBI], ≥2.5) using multiple anti-human secondary antibodies and end-titers were calculated if sufficient sample volume. Correlation of CSF MOG-IgG IBI and titer was assessed. RESULTS: The pan-IgG Fc-specific secondary was optimal, yielding CSF MOG-IgG sensitivity of 90% and specificity of 98% (Youden's index 0.88). CSF MOG-IgG was positive in: 4/282 (1.4%) controls; 66/74 (89%) serum MOG-IgG positive MOGAD patients; and 9/73 (12%) serum MOG-IgG negative patients with high-risk phenotypes. Serum negative but CSF positive MOG-IgG accounted for 9/83 (11%) MOGAD patients, and all fulfilled 2023 MOGAD diagnostic criteria. Subgroup analysis of serum MOG-IgG low-positives revealed CSF MOG-IgG positivity more in MOGAD (13/16[81%]) than other diseases with false positive serum MOG-IgG (3/15[20%]) (p = 0.01). CSF MOG-IgG IBI and CSF MOG-IgG titer (both available in 29 samples) were correlated (Spearman's r = 0.64, p < 0.001). INTERPRETATION: CSF MOG-IgG testing has diagnostic utility in patients with a suspicious phenotype but negative serum MOG-IgG, and those with low positive serum MOG-IgG results and diagnostic uncertainty. These findings support a role for CSF MOG-IgG testing in the appropriate clinical setting. ANN NEUROL 2024;96:34-45.

Caudate functional networks influence brain structural changes with aging.

Neurogenesis decline with aging may be associated with brain atrophy. Subventricular zone neuron precursor cells possibly modulate striatal neuronal activity via the release of soluble molecules. Neurogenesis decay in the subventricular zone may result in structural alterations of brain regions connected to the caudate, particularly to its medial component. The aim of this study was to investigate how the functional organization of caudate networks relates to structural brain changes with aging. One hundred and fifty-two normal subjects were recruited: 52 young healthy adults (≤35 years old), 42 middle-aged (36 ≤ 60 years old) and 58 elderly subjects (≥60 years old). In young adults, stepwise functional connectivity was used to characterize regions that connect to the medial and lateral caudate at different levels of link-step distances. A statistical comparison between the connectivity of medial and lateral caudate in young subjects was useful to define medial and lateral caudate connected regions. Atrophy of medial and lateral caudate connected regions was estimated in young, middle-aged and elderly subjects using T1-weighted images. Results showed that middle-aged and elderly adults exhibited decreased stepwise functional connectivity at one-link step from the caudate, particularly in the frontal, parietal, temporal and occipital brain regions, compared to young subjects. Elderly individuals showed increased stepwise functional connectivity in frontal, parietal, temporal and occipital lobes compared to both young and middle-aged adults. Additionally, elderly adults displayed decreased stepwise functional connectivity compared to middle-aged subjects in specific parietal and subcortical areas. Moreover, in young adults, the medial caudate showed higher direct connectivity to the basal ganglia (left thalamus), superior, middle and inferior frontal and inferior parietal gyri (medial caudate connected region) relative to the lateral caudate. Considering the opposite contrast, lateral caudate showed stronger connectivity to the basal ganglia (right pallidum), orbitofrontal, rostral anterior cingulate and insula cortices (lateral caudate connected region) compared to medial caudate. In elderly subjects, the medial caudate connected region showed greater atrophy relative to the lateral caudate connected region. Brain regions linked to the medial caudate appear to be more vulnerable to aging than lateral caudate connected areas. The adjacency to the subventricular zone may, at least partially, explain these findings. Stepwise functional connectivity analysis can be useful to evaluate the role of the subventricular zone in network disruptions in age-related neurodegenerative disorders.

Functional correlates of cognitive abilities vary with age in pediatric multiple sclerosis.

BACKGROUND: Pediatric multiple sclerosis (PedMS) can hamper brain maturation. Aim of this study was to assess the neuropsychological profile of PedMS patients and their resting-state functional connectivity (RS FC). METHODS: We assessed intelligence quotient (IQ), executive speed, and language in 76 PedMS patients. On a 3.0T scanner RS FC of brain networks was estimated with a seed-based analysis (subset of 58 right-handed PedMS patients and 22 matched healthy controls). Comparisons were run between controls and PedMS (whole cohort and by age). RESULTS: Ninety-five% of patients had normal IQ. The highest rate of failure was observed in executive speed. PedMS showed reduced RS FC in all networks than controls, especially in the basal ganglia. In younger patients (<16-year-old, n = 32) reduced RS FC in the basal ganglia, language, and sensorimotor networks associated with poorer cognitive performance (p < 0.05; r range: 0.39; 0.56). Older patients (≥16-year-old, n = 26) showed increased RS FC in the basal ganglia, default-mode, sensorimotor, executive, and language networks, associated with poorer performance in executive speed and language abilities (p < 0.05; r range: -0.40; -0.59). In both groups, lower RS FC of the caudate nucleus associated with poorer executive speed. CONCLUSIONS: The effect of PedMS on RS FC is clinically relevant and differs according to patients' age.

Understanding the Pathophysiology and Magnetic Resonance Imaging of Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders.

Magnetic resonance imaging (MRI) has been extensively applied in the study of multiple sclerosis (MS), substantially contributing to diagnosis, differential diagnosis, and disease monitoring. MRI studies have significantly contributed to the understanding of MS through the characterization of typical radiological features and their clinical or prognostic implications using conventional MRI pulse sequences and further with the application of advanced imaging techniques sensitive to microstructural damage. Interpretation of results has often been validated by MRI-pathology studies. However, the application of MRI techniques in the study of neuromyelitis optica spectrum disorders (NMOSD) remains an emerging field, and MRI studies have focused on radiological correlates of NMOSD and its pathophysiology to aid in diagnosis, improve monitoring, and identify relevant prognostic factors. In this review, we discuss the main contributions of MRI to the understanding of MS and NMOSD, focusing on the most novel discoveries to clarify differences in the pathophysiology of focal inflammation initiation and perpetuation, involvement of normal-appearing tissue, potential entry routes of pathogenic elements into the CNS, and existence of primary or secondary mechanisms of neurodegeneration.

Timing and Predictors of T2-Lesion Resolution in Patients With Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

OBJECTIVES: To determine the timing and predictors of T2-lesion resolution in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). METHODS: This retrospective observational study using standard-of-care data had inclusion criteria of MOGAD diagnosis, ≥2 MRIs 12 months apart, and ≥1 brain/spinal cord T2-lesion. The median (interquartile range [IQR]) number of MRIs (82% at disease onset) per-patient were: brain, 5 (2-8); spine, 4 (2-8). Predictors of T2-lesion resolution were assessed with age- and sex-adjusted generalized estimating equations and stratified by T2-lesion size (small <1 cm; large ≥1 cm). RESULTS: We studied 583 T2-lesions (brain, 512 [88%]; spinal cord, 71 [12%]) from 55 patients. At last MRI (median follow-up 54 months [IQR 7-74]) 455 T2-lesions (78%) resolved. The median (IQR) time to resolution was 3 months (1.4-7.0). Small T2-lesions resolved more frequently and faster than large T2-lesions. Acute T1-hypointensity decreased the likelihood (odds ratio [95% CI]) of T2-lesion resolution independent of size (small: 0.23 [0.09-0.60], p = 0.002; large: 0.30 [0.16-0.55], p < 0.001), whereas acute steroids favored resolution of large T2-lesions (1.75 [1.01-3.03], p = 0.046). Notably, 32/55 (58%) T2-lesions resolved without treatment. DISCUSSION: The high frequency of spontaneous T2-lesion resolution suggests that this represents MOGAD's natural history. The speed of T2-lesion resolution and influence of size, corticosteroids, and T1-hypointensity on this phenomenon gives insight into MOGAD pathogenesis.

Cognitive function in primary and secondary progressive multiple sclerosis: A multiparametric magnetic resonance imaging study.

BACKGROUND AND PURPOSE: The differences in cognitive function between primary progressive and secondary progressive multiple sclerosis (MS) remain unclear. We compared cognitive performance between primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS), and explored the structural and functional magnetic resonance imaging (MRI) correlates of their cognitive functions. METHODS: Seventy-five healthy controls and 183 MS patients (60 PPMS and 123 SPMS) underwent 3.0-T MRI. MS patients were administered the Brief Repeatable Battery of Neuropsychological Tests; cognitive domain z-scores were calculated and then averaged to obtain a measure of global cognition. Using hierarchical linear regression analysis, the contribution of lesion volumes, normalized brain volumes, white matter (WM) fractional anisotropy (FA) and mean diffusivity abnormalities, and resting state (RS) functional connectivity (FC) alterations to global cognition in PPMS and SPMS was investigated. RESULTS: PPMS and SPMS had similar z-scores in all investigated cognitive domains. Poor global cognitive function was associated with decreased FA of the medial lemniscus (ΔR 2 = 0.11, p = 0.011) and lower normalized gray matter volume (ΔR 2 = 0.29, p < 0.001) in PPMS, and with decreased FA of the fornix (ΔR 2 = 0.35, p < 0.001) and lower normalized WM volume (ΔR 2 = 0.05; p = 0.034) in SPMS. CONCLUSIONS: PPMS and SPMS had similar neuropsychological performance. Cognitive dysfunction in PPMS and SPMS was related to distinct patterns of structural MRI abnormalities and involvement of different WM tracts, whereas RS FC alterations did not contribute to explaining their global cognitive functioning.

Marked central canal T2-hyperintensity in MOGAD myelitis and comparison to NMOSD and MS.

OBJECTIVE: To assess marked central canal T2-hyperintensity in patients with myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) myelitis compared to myelitis patients with aquaporin-4-antibody-positive neuromyelitis optica spectrum disorder (AQP4 + NMOSD) and multiple sclerosis (MS). MATERIAL/METHODS: Two blinded raters evaluated spinal cord magnetic resonance imaging (MRIs) of myelitis patients with MOGAD (n = 63), AQP4 + NMOSD (n = 37), and MS (n = 26), assessing for marked central canal T2-hyperintensity and its evolution. If there were conflicting results, a third neurologist assessed the MRI. RESULTS: Marked central canal T2-hyperintensity was more frequent in patients with MOGAD (18/63[29%]) than MS (1/26[4%]; p = 0.01) myelitis but did not differ from AQP4 + NMOSD (13/37[35%]; p = 0.49). Marked central canal T2-hyperintensity had completely resolved on follow-up axial MRI for most MOGAD (12/14[86%]) and AQP4 + NMOSD (10/10[100%]; p = 0.49) patients. CONCLUSIONS: Marked central canal T2-hyperintensity is a common transient radiologic accompaniment of MOGAD and AQP4 + NMOSD myelitis, but not MS myelitis.

Cerebral enhancement in MOG antibody-associated disease.

INTRODUCTION: Limited data exist on brain MRI enhancement in myelin-oligodendrocyte-glycoprotein (MOG) antibody-associated disease (MOGAD) and differences from aquaporin-4-IgG-positive-neuromyelitis-optica-spectrum-disorder (AQP4+NMOSD), and multiple sclerosis (MS). METHODS: In this retrospective observational study, we identified 122 Mayo Clinic MOGAD patients (1 January 1996-1 July 2020) with cerebral attacks. We explored enhancement patterns using a discovery set (n=41). We assessed enhancement frequency and Expanded Disability Status Scale scores at nadir and follow-up in the remainder (n=81). Two raters assessed T1-weighted-postgadolinium MRIs (1.5T/3T) for enhancement patterns in MOGAD, AQP4+NMOSD (n=14) and MS (n=26). Inter-rater agreement was assessed. Leptomeningeal enhancement clinical correlates were analysed. RESULTS: Enhancement occurred in 59/81 (73%) MOGAD cerebral attacks but did not influence outcome. Enhancement was often patchy/heterogeneous in MOGAD (33/59 (56%)), AQP4+NMOSD (9/14 (64%); p=0.57) and MS (16/26 (62%); p=0.63). Leptomeningeal enhancement favoured MOGAD (27/59 (46%)) over AQP4+NMOSD (1/14 (7%); p=0.01) and MS (1/26 (4%); p<0.001) with headache, fever and seizures frequent clinical correlates. Ring enhancement favoured MS (8/26 (31%); p=0.006) over MOGAD (4/59 (7%)). Linear ependymal enhancement was unique to AQP4+NMOSD (2/14 (14%)) and persistent enhancement (>3 months) was rare (0%-8%) across all groups. Inter-rater agreement for enhancement patterns was moderate. CONCLUSIONS: Enhancement is common with MOGAD cerebral attacks and often has a non-specific patchy appearance and rarely persists beyond 3 months. Leptomeningeal enhancement favours MOGAD over AQP4+NMOSD and MS.

Comparison of MRI T2-lesion evolution in pediatric MOGAD, NMOSD, and MS.

BACKGROUND: Magnetic resonance imaging (MRI) T2-lesions resolve more often in myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) than aquaporin-4 IgG-positive neuromyelitis optica spectrum disorder (AQP4 + NMOSD) and multiple sclerosis (MS) in adults but few studies analyzed children. OBJECTIVE: The main objective of this study is to investigate MRI T2-lesion evolution in pediatric MOGAD, AQP4 + NMOSD, and MS. METHODS: Inclusion criteria were as follows: (1) first clinical attack; (2) abnormal MRI (⩽6 weeks); (3) follow-up MRI beyond 6 months without relapses in that region; and (4) age < 18 years. An index T2-lesion (symptomatic/largest) was identified, and T2-lesion resolution or persistence on follow-up MRI was determined. RESULTS: We included 56 patients (MOGAD, 21; AQP4 + NMOSD, 8; MS, 27) with 69 attacks. Index T2-lesion resolution was more frequent in MOGAD (brain 9 of 15 [60%]; spine 8 of 12 [67%]) than AQP4 + NMOSD (brain 1 of 4 [25%]; spine 0 of 7 [0%]) and MS (brain 0 of 18 [0%]; spine 1 of 13 [8%]), p < 0.01. Resolution of all T2-lesions occurred more often in MOGAD (brain 6 of 15 [40%]; spine 7 of 12 [58%]) than AQP4 + NMOSD (brain 1 of 4 [25%]; spine 0 of 7 [0%]), and MS (brain 0 of 18 [0%]; spine 1 of 13 [8%]), p < 0.01. Reductions in median index T2-lesion area were greater in MOGAD (brain, 305 mm; spine, 23 mm) than MS (brain, 42 mm [p<0.001]; spine, 10 mm [p<0.001]) without differing from AQP4 + NMOSD (brain, 133 mm [p=0.42]; spine, 19.5 mm [p=0.69]). CONCLUSION: In children, MRI T2-lesions resolved more often in MOGAD than AQP4 + NMOSD and MS which is similar to adults suggesting these differences are related to pathogenesis rather than age.

Tumefactive Demyelination in MOG Ab-Associated Disease, Multiple Sclerosis, and AQP-4-IgG-Positive Neuromyelitis Optica Spectrum Disorder.

BACKGROUND AND OBJECTIVES: Studies on tumefactive brain lesions in myelin oligodendrocyte glycoprotein-immunoglobulin G (IgG)-associated disease (MOGAD) are lacking. We sought to characterize the frequency clinical, laboratory, and MRI features of these lesions in MOGAD and compare them with those in multiple sclerosis (MS) and aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD). METHODS: We retrospectively searched 194 patients with MOGAD and 359 patients with AQP4+NMOSD with clinical/MRI details available from the Mayo Clinic databases and included those with ≥1 tumefactive brain lesion (maximum transverse diameter ≥2 cm) on MRI. Patients with tumefactive MS were identified using the Mayo Clinic medical record linkage system. Binary multivariable stepwise logistic regression identified independent predictors of MOGAD diagnosis; Cox proportional regression models were used to assess the risk of relapsing disease and gait aid in patients with tumefactive MOGAD vs those with nontumefactive MOGAD. RESULTS: We included 108 patients with tumefactive demyelination (MOGAD = 43; AQP4+NMOSD = 16; and MS = 49). Tumefactive lesions were more frequent among those with MOGAD (43/194 [22%]) than among those with AQP4+NMOSD (16/359 [5%], p < 0.001). Risk of relapse and need for gait aid were similar in tumefactive and nontumefactive MOGAD. Clinical features more frequent in MOGAD than in MS included headache (18/43 [42%] vs 10/49 [20%]; p = 0.03) and somnolence (12/43 [28%] vs 2/49 [4%]; p = 0.003), the latter also more frequent than in AQP4+NMOSD (0/16 [0%]; p = 0.02). The presence of peripheral T2-hypointense rim, T1-hypointensity, diffusion restriction (particularly an arc pattern), ring enhancement, and Baló-like or cystic appearance favored MS over MOGAD (p ≤ 0.001). MRI features were broadly similar in MOGAD and AQP4+NMOSD, except for more frequent diffusion restriction in AQP4+NMOSD (10/15 [67%]) than in MOGAD (11/42 [26%], p = 0.005). CSF analysis revealed less frequent positive oligoclonal bands in MOGAD (2/37 [5%]) than in MS (30/43 [70%], p < 0.001) and higher median white cell count in MOGAD than in MS (33 vs 6 cells/µL, p < 0.001). At baseline, independent predictors of MOGAD diagnosis were the presence of somnolence/headache, absence of T2-hypointense rim, lack of T1-hypointensity, and no diffusion restriction (Nagelkerke R 2 = 0.67). Tumefactive lesion resolution was more common in MOGAD than in MS or AQP4+NMOSD and improved model performance. DISCUSSION: Tumefactive lesions are frequent in MOGAD but not associated with a worse prognosis. The clinical, MRI, and CSF attributes of tumefactive MOGAD differ from those of tumefactive MS and are more similar to those of tumefactive AQP4+NMOSD with the exception of lesion resolution, which favors MOGAD.

Clinical and MRI measures to identify non-acute MOG-antibody disease in adults.

MRI and clinical features of myelin oligodendrocyte glycoprotein (MOG)-antibody disease may overlap with those of other inflammatory demyelinating conditions posing diagnostic challenges, especially in non-acute phases and when serologic testing for MOG antibodies is unavailable or shows uncertain results. We aimed to identify MRI and clinical markers that differentiate non-acute MOG-antibody disease from aquaporin 4 (AQP4)-antibody neuromyelitis optica spectrum disorder and relapsing remitting multiple sclerosis, guiding in the identification of patients with MOG-antibody disease in clinical practice. In this cross-sectional retrospective study, data from 16 MAGNIMS centres were included. Data collection and analyses were conducted from 2019 to 2021. Inclusion criteria were: diagnosis of MOG-antibody disease; AQP4-neuromyelitis optica spectrum disorder and multiple sclerosis; brain and cord MRI at least 6 months from relapse; and Expanded Disability Status Scale (EDSS) score on the day of MRI. Brain white matter T2 lesions, T1-hypointense lesions, cortical and cord lesions were identified. Random forest models were constructed to classify patients as MOG-antibody disease/AQP4-neuromyelitis optica spectrum disorder/multiple sclerosis; a leave one out cross-validation procedure assessed the performance of the models. Based on the best discriminators between diseases, we proposed a guide to target investigations for MOG-antibody disease. One hundred and sixty-two patients with MOG-antibody disease [99 females, mean age: 41 (±14) years, median EDSS: 2 (0-7.5)], 162 with AQP4-neuromyelitis optica spectrum disorder [132 females, mean age: 51 (±14) years, median EDSS: 3.5 (0-8)], 189 with multiple sclerosis (132 females, mean age: 40 (±10) years, median EDSS: 2 (0-8)] and 152 healthy controls (91 females) were studied. In young patients (<34 years), with low disability (EDSS < 3), the absence of Dawson's fingers, temporal lobe lesions and longitudinally extensive lesions in the cervical cord pointed towards a diagnosis of MOG-antibody disease instead of the other two diseases (accuracy: 76%, sensitivity: 81%, specificity: 84%, P < 0.001). In these non-acute patients, the number of brain lesions < 6 predicted MOG-antibody disease versus multiple sclerosis (accuracy: 83%, sensitivity: 82%, specificity: 83%, P < 0.001). An EDSS < 3 and the absence of longitudinally extensive lesions in the cervical cord predicted MOG-antibody disease versus AQP4-neuromyelitis optica spectrum disorder (accuracy: 76%, sensitivity: 89%, specificity: 62%, P < 0.001). A workflow with sequential tests and supporting features is proposed to guide better identification of patients with MOG-antibody disease. Adult patients with non-acute MOG-antibody disease showed distinctive clinical and MRI features when compared to AQP4-neuromyelitis optica spectrum disorder and multiple sclerosis. A careful inspection of the morphology of brain and cord lesions together with clinical information can guide further analyses towards the diagnosis of MOG-antibody disease in clinical practice.

Neural precursor cells tune striatal connectivity through the release of IGFBPL1.

The adult brain retains over life endogenous neural stem/precursor cells (eNPCs) within the subventricular zone (SVZ). Whether or not these cells exert physiological functions is still unclear. In the present work, we provide evidence that SVZ-eNPCs tune structural, electrophysiological, and behavioural aspects of striatal function via secretion of insulin-like growth factor binding protein-like 1 (IGFBPL1). In mice, selective ablation of SVZ-eNPCs or selective abrogation of IGFBPL1 determined an impairment of striatal medium spiny neuron morphology, a higher failure rate in GABAergic transmission mediated by fast-spiking interneurons, and striatum-related behavioural dysfunctions. We also found IGFBPL1 expression in the human SVZ, foetal and induced-pluripotent stem cell-derived NPCs. Finally, we found a significant correlation between SVZ damage, reduction of striatum volume, and impairment of information processing speed in neurological patients. Our results highlight the physiological role of adult SVZ-eNPCs in supporting cognitive functions by regulating striatal neuronal activity.

Neuroimaging features in inflammatory myelopathies: A review.

Spinal cord involvement can be observed in the course of immune-mediated disorders. Although multiple sclerosis (MS) represents the leading cause of inflammatory myelopathy, an increasing number of alternative etiologies must be now considered in the diagnostic work-up of patients presenting with myelitis. These include antibody-mediated disorders and cytotoxic T cell-mediated diseases targeting central nervous system (CNS) antigens, and systemic autoimmune conditions with secondary CNS involvement. Even though clinical features are helpful to orient the diagnostic suspicion (e.g., timing and severity of myelopathy symptoms), the differential diagnosis of inflammatory myelopathies is often challenging due to overlapping features. Moreover, noninflammatory etiologies can sometimes mimic an inflammatory process. In this setting, magnetic resonance imaging (MRI) is becoming a fundamental tool for the characterization of spinal cord damage, revealing a pictorial scenario which is wider than the clinical manifestations. The characterization of spinal cord lesions in terms of longitudinal extension, location on axial plane, involvement of the white matter and/or gray matter, and specific patterns of contrast enhancement, often allows a proper differentiation of these diseases. For instance, besides classical features, such as the presence of longitudinally extensive spinal cord lesions in patients with aquaporin-4-IgG positive neuromyelitis optica spectrum disorder (AQP4+NMOSD), novel radiological signs (e.g., H sign, trident sign) have been recently proposed and successfully applied for the differential diagnosis of inflammatory myelopathies. In this review article, we will discuss the radiological features of spinal cord involvement in autoimmune disorders such as MS, AQP4+NMOSD, myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and other recently characterized immune-mediated diseases. The identification of imaging pitfalls and mimics that can lead to misdiagnosis will also be examined. Since spinal cord damage is a major cause of irreversible clinical disability, the recognition of these radiological aspects will help clinicians achieve a correct and prompt diagnosis, treat early with disease-specific treatment and improve patient outcomes.

Myelitis features and outcomes in CNS demyelinating disorders: Comparison between multiple sclerosis, MOGAD, and AQP4-IgG-positive NMOSD.

Inflammatory myelopathies can manifest with a combination of motor, sensory and autonomic dysfunction of variable severity. Depending on the underlying etiology, the episodes of myelitis can recur, often leading to irreversible spinal cord damage and major long-term disability. Three main demyelinating disorders of the central nervous system, namely multiple sclerosis (MS), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders (AQP4+NMOSD) and myelin oligodendrocyte glycoprotein-IgG associated disease (MOGAD), can induce spinal cord inflammation through different pathogenic mechanisms, resulting in a more or less profound disruption of spinal cord integrity. This ultimately translates into distinctive clinical-MRI features, as well as distinct patterns of disability accrual, with a step-wise worsening of neurological function in MOGAD and AQP4+NMOSD, and progressive disability accrual in MS. Early recognition of the specific etiologies of demyelinating myelitis and initiation of the appropriate treatment is crucial to improve outcome. In this review article we summarize and compare the clinical and imaging features of spinal cord involvement in these three demyelinating disorders, both during the acute phase and over time, and outline the current knowledge on the expected patterns of disability accrual and outcomes. We also discuss the potential implications of these observations for patient management and counseling.

Frequency of New or Enlarging Lesions on MRI Outside of Clinical Attacks in Patients With MOG-Antibody-Associated Disease.

OBJECTIVE: To determine the frequency of new or enlarging T2-hyperintense or enhancing lesions outside of clinical attacks in myelin-oligodendrocyte-glycoprotein-antibody-associated-disease (MOGAD) versus multiple sclerosis (MS) and aquaporin-4 antibody-positive-neuromyelitis-optica-spectrum-disorder (AQP4+NMOSD). DESIGN/METHODS: We retrospectively included Mayo Clinic MOGAD patients with: 1) MOG-IgG positivity by live-cell-based-assay; 2) Fulfilling proposed MOGAD diagnostic criteria; 3) Baseline and follow-up paired MRIs without interval attacks. A neurologist and neuroradiologist reviewed MRIs (T2-FLAIR brain, T2 spine, and T1-post-gadolinium brain and spine) to identify new or enlarging lesions. A MOGAD subset was then compared to MS and AQP4+NMOSD patients, based on broadly similar inter-scan intervals. RESULTS: We included 105 MOGAD patients (median age, 31 years[range, 2-80]; 60% female) with 373 paired MRIs. In total, 10/105 (9.5%) patients and 13/373 (3%) scans had one or more new T2-lesions (brain, 12/213[6%]; spine, 1/160[0.6%]) and 8/367 (2%) had enhancing lesions. New brain lesions were less in MOGAD (1/25[4%]) than MS (14/26[54%], p<0.0001) but did not differ from AQP4+NMOSD (1/13[8%], p=1.0) in subgroup analysis. New spinal lesions were rare across groups (0-4%). CONCLUSIONS: New or enlarging MRI lesions rarely develop outside of clinical attacks in MOGAD differing from MS. Surveillance MRIs in MOGAD have limited utility with implications for clinical practice and trial design.

Time-varying connectivity of the precuneus and its association with cognition and depressive symptoms in neuromyelitis optica: A pilot MRI study.

BACKGROUND: The precuneus is involved in cognition and depression; static functional connectivity (SFC) abnormalities of this region have been observed in neuromyelitis optica spectrum disorders (NMOSD). Time-varying functional connectivity (TVC) underpins dynamic variations of brain connectivity. OBJECTIVE: The aim of this study was to explore precuneus SFC and TVC in NMOSD patients and their associations with neuropsychological features. METHODS: This retrospective study includes 27 NMOSD patients and 30 matched healthy controls undergoing resting state functional magnetic resonance imaging (MRI) and a neuropsychological evaluation of cognitive performance and depressive symptoms. A sliding-window correlation analysis using bilateral precuneus as seed region assessed TVC, which was quantified by the standard deviation of connectivity across windows. Mean connectivity indicated SFC. RESULTS: Compared to controls, patients had reduced SFC between precuneus, temporal lobe, putamen and cerebellum, and reduced TVC between precuneus and prefronto-parietal-temporo-occipital cortices and caudate. Patients also had increased intra-precuneal TVC and increased TVC between the precuneus and the temporal cortex. More severe depressive symptoms correlated with increased TVC between the precuneus and the temporal lobe; worse cognitive performance mainly correlated with higher TVC between the precuneus and the parietal lobe. CONCLUSION: TVC rather than SFC of the precuneus correlates with NMOSD neuropsychological features; different TVC abnormalities underlie depressive symptoms and cognitive impairment.