Atypical Demyelinating Disorders: MR Imaging Features, Atypical Triggers, and Etiopathogenesis.

Atypical demyelinating lesions (ADLs) can be idiopathic, occurring as isolated and self-limited events, or can appear in different stages of relapsing demyelinating diseases. Not infrequently, ADLs occur in inflammatory syndromes associated with exogenous or endogenous toxic factors, metabolic imbalance, or infectious agents. It is important to recognize imaging patterns that indicate an inflammatory/demyelinating substrate in central nervous system lesions and to investigate potential triggers or complicating factors that might be associated. The prognostic and treatment strategies of ADLs are influenced by the underlying etiopathogenesis.

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.

The new era of artificial intelligence in neuroradiology: current research and promising tools.

Radiology has a number of characteristics that make it an especially suitable medical discipline for early artificial intelligence (AI) adoption. These include having a well-established digital workflow, standardized protocols for image storage, and numerous well-defined interpretive activities. The more than 200 commercial radiologic AI-based products recently approved by the Food and Drug Administration (FDA) to assist radiologists in a number of narrow image-analysis tasks such as image enhancement, workflow triage, and quantification, corroborate this observation. However, in order to leverage AI to boost efficacy and efficiency, and to overcome substantial obstacles to widespread successful clinical use of these products, radiologists should become familiarized with the emerging applications in their particular areas of expertise. In light of this, in this article we survey the existing literature on the application of AI-based techniques in neuroradiology, focusing on conditions such as vascular diseases, epilepsy, and demyelinating and neurodegenerative conditions. We also introduce some of the algorithms behind the applications, briefly discuss a few of the challenges of generalization in the use of AI models in neuroradiology, and skate over the most relevant commercially available solutions adopted in clinical practice. If well designed, AI algorithms have the potential to radically improve radiology, strengthening image analysis, enhancing the value of quantitative imaging techniques, and mitigating diagnostic errors.

A radiologia tem uma série de características que a torna uma disciplina médica especialmente adequada à adoção precoce da inteligência artificial (IA), incluindo um fluxo de trabalho digital bem estabelecido, protocolos padronizados para armazenamento de imagens e inúmeras atividades interpretativas bem definidas. Tal adequação é corroborada pelos mais de 200 produtos radiológicos comerciais baseados em IA recentemente aprovados pelo Food and Drug Administration (FDA) para auxiliar os radiologistas em uma série de tarefas restritas de análise de imagens, como quantificação, triagem de fluxo de trabalho e aprimoramento da qualidade das imagens. Entretanto, para o aumento da eficácia e eficiência da IA, além de uma utilização clínica bem-sucedida dos produtos que utilizam essa tecnologia, os radiologistas devem estar atualizados com as aplicações em suas áreas específicas de atuação. Assim, neste artigo, pesquisamos na literatura existente aplicações baseadas em IA em neurorradiologia, mais especificamente em condições como doenças vasculares, epilepsia, condições desmielinizantes e neurodegenerativas. Também abordamos os principais algoritmos por trás de tais aplicações, discutimos alguns dos desafios na generalização no uso desses modelos e introduzimos as soluções comercialmente disponíveis mais relevantes adotadas na prática clínica. Se cautelosamente desenvolvidos, os algoritmos de IA têm o potencial de melhorar radicalmente a radiologia, aperfeiçoando a análise de imagens, aumentando o valor das técnicas de imagem quantitativas e mitigando erros de diagnóstico.

T1/T2-weighted ratio: A feasible MRI biomarker in multiple sclerosis.

T1/T2-weighted ratio is a novel magnetic resonance imaging (MRI) biomarker based on conventional sequences, related to microstructural integrity and with increasing use in multiple sclerosis (MS) research. Different from other advanced MRI techniques, this method has the advantage of being based on routinely acquired MRI sequences, a feature that enables analysis of retrospective cohorts with considerable clinical value. This article provides an overview of this method, describing the previous cross-sectional and longitudinal findings in the main MS clinical phenotypes and in different brain tissues: focal white matter (WM) lesions, normal-appearing white matter (NAWM), cortical gray matter (GM), and deep normal-appearing gray matter (NAGM). We also discuss the clinical associations, possible reasons for conflicting results, correlations with other MRI-based measures, and histopathological associations. We highlight the limitations of the biomarker itself and the methodology of each study. Finally, we update the reader on its potential use as an imaging biomarker in research.

Misdiagnosis in multiple sclerosis in a Brazilian reference center: Clinical, radiological, laboratory profile and failures in the diagnostic process-Cohort study.

BACKGROUND: Multiple sclerosis misdiagnosis remains a problem despite the well-validated McDonald 2017. For proper evaluation of errors in the diagnostic process that lead to misdiagnosis, it is adequate to incorporate patients who are already under regular follow-up at reference centers of demyelinating diseases. OBJECTIVES: To evaluate multiple sclerosis misdiagnosis in patients who are on follow-up at a reference center of demyelinating diseases in Brazil. METHODS: We designed an observational study including patients in regular follow-up, who were diagnosed with multiple sclerosis at our specialized outpatient clinic in the Hospital of Clinics in the University of Sao Paulo, from 1996 to 2021, and were reassessed for misdiagnosis in 2022. We evaluated demographic information, clinical profile, and complementary exams and classified participants as "established multiple sclerosis," "non-multiple sclerosis, diagnosed," and "non-multiple sclerosis, undiagnosed." Failures in the diagnostic process were assessed by the modified Diagnostic Error Evaluation and Research tool. RESULTS: A total of 201 patients were included. After analysis, 191/201 (95.02%) participants were confirmed as "established multiple sclerosis," 5/201 (2.49%) were defined as "non-multiple sclerosis, diagnosed," and 5/201 (2.49%) were defined as "non-multiple sclerosis, undiagnosed." CONCLUSIONS: Multiple sclerosis misdiagnosis persists in reference centers, emphasizing the need for careful interpretation of clinical findings to prevent errors.

AQP4-IgG NMOSD, MOGAD, and double-seronegative NMOSD: is it possible to depict the antibody subtype using magnetic resonance imaging?

BACKGROUND: There is clinical and radiological overlap among demyelinating diseases. However, their pathophysiological mechanisms are different and carry distinct prognoses and treatment demands. OBJECTIVE: To investigate magnetic resonance imaging (MRI) features of patients with myelin-oligodendrocyte glycoprotein associated disease (MOGAD), antibody against aquaporin-4(AQP-4)-immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG NMOSD), and double-seronegative patients. METHODS: A cross-sectional retrospective study was performed to analyze the topography and morphology of central nervous system (CNS) lesions. Two neuroradiologists consensually analyzed the brain, orbit, and spinal cord images. RESULTS: In total, 68 patients were enrolled in the study (25 with AQP4-IgG-positive NMOSD, 28 with MOGAD, and 15 double-seronegative patients). There were differences in clinical presentation among the groups. The MOGAD group had less brain involvement (39.2%) than the NMOSD group (p = 0.002), mostly in the subcortical/juxtacortical, the midbrain, the middle cerebellar peduncle, and the cerebellum. Double-seronegative patients had more brain involvement (80%) with larger and tumefactive lesion morphology. In addition, double-seronegative patients showed the longest optic neuritis (p = 0.006), which was more prevalent in the intracranial optic nerve compartment. AQP4-IgG-positive NMOSD optic neuritis had a predominant optic-chiasm location, and brain lesions mainly affected hypothalamic regions and the postrema area (MOGAD versus AQP4-IgG-positive NMOSD, p= 0 .013). Furthermore, this group had more spinal cord lesions (78.3%), and bright spotty lesions were a paramount finding to differentiate it from MOGAD (p = 0.003). CONCLUSION: The pooled analysis of lesion topography, morphology, and signal intensity provides critical information to help clinicians form a timely differential diagnosis.

ANTECEDENTES: Há sobreposição clínica e radiológica entre as doenças desmielinizantes. No entanto, seus mecanismos fisiopatológicos são diferentes e apresentam prognósticos e demandas de tratamento distintos. OBJETIVO: Investigar as características de imagens de RM dos pacientes com doença associada à glicoproteína de oligodendrócito de mielina (MOGAD), a doenças do espectro da neuromielite óptica positivas para antiaquaporina-4 imunoglobulina G (AQP4-IgG NMOSD), e pacientes duplamente soronegativos. MéTODOS: Estudo retrospectivo e transversal para analisar as características e frequência das lesões do sistema nervoso central (SNC). Dois neurorradiologistas avaliaram consensualmente as imagens do cérebro, das órbitas e da medula espinhal. RESULTADOS: Ao todo, foram incluídos 68 pacientes(25 com AQP4-IgG NMOSD, 28 com MOGAD e 15 duplo-soronegativos). Há diferenças na apresentação clínica entre os grupos. O grupo MOGAD demonstrou menor frequência de comprometimento do cérebro (39.2%) comparado com o AQP4-IgG NMOSD (p = 0.002), com predomínio da distribuição das lesões nas regiões subcortical/justacortical, mesencéfalo, pedúnculos cerebelares médios e cerebelo. O grupo duplo-soronegativo demonstrou maior frequência de comprometimento do cérebro (80%), com lesões de maiores dimensões e com morfologia tumefeita, além de neurite óptica com maior extensão (p = 0.006). O grupo AQP4-IgG NMOSD demonstrou neurite óptica com predomínio na região óptico-quiasmática e as lesões encefálicas acometeram predominantemente as regiões hipotalâmica e área postrema (MOGAD versus AQP4-IgG NMOSD p = 0.013). Além disso, foram observadas mais lesões na medula espinhal (78.3%) e a presença da "bright spotty lesion" foi um achado primordial para a sua diferenciação com os pacientes MOGAD (p = 0.003). CONCLUSãO: A análise pormenorizada das características das lesões por RM dos pacientes com doenças desmielinizantes imunomediadas fornece informações fundamentais que auxiliam os médicos no diagnóstico diferencial em um momento oportuno.

Real-world application of the 2022 diagnostic criteria for first-ever episode of optic neuritis.

Optic neuritis (ON) admits diverse differential diagnoses. Petzold proposed diagnostic criteria for ON in 2022, although real-world application of these criteria is missing. We conducted a retrospective review of patients with ON. We classified patients into definite or possible ON, and into groups A (typical neuritis), B (painless), or C (binocular) and estimated the frequency of etiologies for each group. We included 77 patients, with 62% definite and 38% possible ON. CRION and NMOSD-AQP4 negative-ON were less commonly seen in definite ON. Application of the 2022 criteria revealed a lower-than-expected frequency of definite ON, particularly for seronegative non-MS causes.

AQP4-IgG NMOSD, MOGAD, and double-seronegative NMOSD: is it possible to depict the antibody subtype using magnetic resonance imaging? / NMOSD AQP4-IgG, MOGAD e NMOSD duplo soronegativo: é possível caracterizar o tipo de anticorpo pela ressonância magnética?

Abstract Background There is clinical and radiological overlap among demyelinating diseases. However, their pathophysiological mechanisms are different and carry distinct prognoses and treatment demands. Objective To investigate magnetic resonance imaging (MRI) features of patients with myelin-oligodendrocyte glycoprotein associated disease (MOGAD), antibody against aquaporin-4(AQP-4)-immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG NMOSD), and double-seronegative patients. Methods A cross-sectional retrospective study was performed to analyze the topography and morphology of central nervous system (CNS) lesions. Two neuroradiologists consensually analyzed the brain, orbit, and spinal cord images. Results In total, 68 patients were enrolled in the study (25 with AQP4-IgG-positive NMOSD, 28 with MOGAD, and 15 double-seronegative patients). There were differences in clinical presentation among the groups. The MOGAD group had less brain involvement (39.2%) than the NMOSD group (p = 0.002), mostly in the subcortical/juxtacortical, the midbrain, the middle cerebellar peduncle, and the cerebellum. Double-seronegative patients had more brain involvement (80%) with larger and tumefactive lesion morphology. In addition, double-seronegative patients showed the longest optic neuritis (p = 0.006), which was more prevalent in the intracranial optic nerve compartment. AQP4-IgG-positive NMOSD optic neuritis had a predominant optic-chiasm location, and brain lesions mainly affected hypothalamic regions and the postrema area (MOGAD versus AQP4-IgG-positive NMOSD, p= 0 .013). Furthermore, this group had more spinal cord lesions (78.3%), and bright spotty lesions were a paramount finding to differentiate it from MOGAD (p = 0.003). Conclusion The pooled analysis of lesion topography, morphology, and signal intensity provides critical information to help clinicians form a timely differential diagnosis.

Resumo Antecedentes Há sobreposição clínica e radiológica entre as doenças desmielinizantes. No entanto, seus mecanismos fisiopatológicos são diferentes e apresentam prognósticos e demandas de tratamento distintos. Objetivo Investigar as características de imagens de RM dos pacientes com doença associada à glicoproteína de oligodendrócito de mielina (MOGAD), a doenças do espectro da neuromielite óptica positivas para antiaquaporina-4 imunoglobulina G (AQP4-IgG NMOSD), e pacientes duplamente soronegativos. Métodos Estudo retrospectivo e transversal para analisar as características e frequência das lesões do sistema nervoso central (SNC). Dois neurorradiologistas avaliaram consensualmente as imagens do cérebro, das órbitas e da medula espinhal. Resultados Ao todo, foram incluídos 68 pacientes(25 com AQP4-IgG NMOSD, 28 com MOGAD e 15 duplo-soronegativos). Há diferenças na apresentação clínica entre os grupos. O grupo MOGAD demonstrou menor frequência de comprometimento do cérebro (39.2%) comparado com o AQP4-IgG NMOSD (p = 0.002), com predomínio da distribuição das lesões nas regiões subcortical/justacortical, mesencéfalo, pedúnculos cerebelares médios e cerebelo. O grupo duplo-soronegativo demonstrou maior frequência de comprometimento do cérebro (80%), com lesões de maiores dimensões e com morfologia tumefeita, além de neurite óptica com maior extensão (p = 0.006). O grupo AQP4-IgG NMOSD demonstrou neurite óptica com predomínio na região óptico-quiasmática e as lesões encefálicas acometeram predominantemente as regiões hipotalâmica e área postrema (MOGAD versus AQP4-IgG NMOSD p = 0.013). Além disso, foram observadas mais lesões na medula espinhal (78.3%) e a presença da "bright spotty lesion" foi um achado primordial para a sua diferenciação com os pacientes MOGAD (p = 0.003). Conclusão A análise pormenorizada das características das lesões por RM dos pacientes com doenças desmielinizantes imunomediadas fornece informações fundamentais que auxiliam os médicos no diagnóstico diferencial em um momento oportuno.

Neuromyelitis optica spectrum disorders: a review with a focus on children and adolescents.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare and severe inflammatory disorder of the central nervous system (CNS). It is strongly associated with anti-aquaporin 4 antibodies (AQP4-IgG), and it mainly affects young women from non-white ethnicities. However, ∼ 5 to 10% of all cases have onset during childhood. Children and adolescents share the same clinical, radiologic, and laboratory presentation as adults. Thus, the same NMOSD diagnostic criteria are also applied to pediatric-onset patients, but data on NMOSD in this population is still scarce. In seronegative pediatric patients, there is a high frequency of the antibody against myelin oligodendrocyte glycoprotein (MOG-IgG) indicating another disease group, but the clinical distinction between these two diseases may be challenging. Three drugs (eculizumab, satralizumab, and inebilizumab) have been recently approved for the treatment of adult patients with AQP4-IgG-positive NMOSD. Only satralizumab has recruited adolescents in one of the two pivotal clinical trials. Additional clinical trials in pediatric NMOSD are urgently required to evaluate the safety and efficacy of these drugs in this population.

O espectro da neuromielite óptica (ENMO) é uma rara e grave doença inflamatória do sistema nervoso central (SNC), fortemente associada ao anticorpo anti-aquaporina 4 (AQP4-IgG) e que afeta preferencialmente mulheres jovens de etnias não-caucasianas. No entanto, aproximadamente de 5 a 10% de todos os casos se iniciam na infância. Crianças e adolescentes compartilham as mesmas características clínicas, radiológicas e laboratoriais dos adultos. Além disso, o mesmo critério diagnóstico de ENMO é aplicado para pacientes com início na infância. No entanto, dados da população pediátrica são escassos. Em pacientes pediátricos soronegativos, existe uma alta frequência de positividade ao anticorpo contra a glicoproteína na mielina do oligodendrócito (MOG-IgG), indicando outra patologia; porém, a distinção clínica entre as duas doenças é desafiadora. Três medicações (eculizumabe, inebilizumabe e satralizumabe) foram recentemente aprovadas para pacientes adultos com AQP4-IgG. Apenas um dos ensaios pivotais do satralizumabe recrutou adolescentes. Novos ensaios clínicos em pacientes pediátricos com ENMO são necessários para avaliar a segurança e eficácia destas drogas nesta população.

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.

Neuromyelitis optica spectrum disorders: a review with a focus on children and adolescents / Espectro da neuromielite óptica: uma revisão com ênfase em crianças e adolescentes

Abstract Neuromyelitis optica spectrum disorder (NMOSD) is a rare and severe inflammatory disorder of the central nervous system (CNS). It is strongly associated with anti-aquaporin 4 antibodies (AQP4-IgG), and it mainly affects young women from non-white ethnicities. However, ~ 5 to 10% of all cases have onset during childhood. Children and adolescents share the same clinical, radiologic, and laboratory presentation as adults. Thus, the same NMOSD diagnostic criteria are also applied to pediatric-onset patients, but data on NMOSD in this population is still scarce. In seronegative pediatric patients, there is a high frequency of the antibody against myelin oligodendrocyte glycoprotein (MOG-IgG) indicating another disease group, but the clinical distinction between these two diseases may be challenging. Three drugs (eculizumab, satralizumab, and inebilizumab) have been recently approved for the treatment of adult patients with AQP4-IgG-positive NMOSD. Only satralizumab has recruited adolescents in one of the two pivotal clinical trials. Additional clinical trials in pediatric NMOSD are urgently required to evaluate the safety and efficacy of these drugs in this population.

Resumo O espectro da neuromielite óptica (ENMO) é uma rara e grave doença inflamatória do sistema nervoso central (SNC), fortemente associada ao anticorpo anti-aquaporina 4 (AQP4-IgG) e que afeta preferencialmente mulheres jovens de etnias não-caucasianas. No entanto, aproximadamente de 5 a 10% de todos os casos se iniciam na infância. Crianças e adolescentes compartilham as mesmas características clínicas, radiológicas e laboratoriais dos adultos. Além disso, o mesmo critério diagnóstico de ENMO é aplicado para pacientes com início na infância. No entanto, dados da população pediátrica são escassos. Em pacientes pediátricos soronegativos, existe uma alta frequência de positividade ao anticorpo contra a glicoproteína na mielina do oligodendrócito (MOG-IgG), indicando outra patologia; porém, a distinção clínica entre as duas doenças é desafiadora. Três medicações (eculizumabe, inebilizumabe e satralizumabe) foram recentemente aprovadas para pacientes adultos com AQP4-IgG. Apenas um dos ensaios pivotais do satralizumabe recrutou adolescentes. Novos ensaios clínicos em pacientes pediátricos com ENMO são necessários para avaliar a segurança e eficácia destas drogas nesta população.

Primary angiitis of the central nervous system as a mimic of multiple sclerosis: A case report.

BACKGROUND: Primary angiitis of the central nervous system is a rare inflammatory vasculopathy and it is a difficult diagnosis to make because of its kaleidoscopic presentation and its multiple mimics, including multiple sclerosis. CASE PRESENTATION: A 21-year-old men presented a four-year history of progressive gait deterioration. Magnetic resonance imaging of the brain and spine showed hyperintense round-shaped lesions on T2 images, many with contrast enhancement, in supra/infratentorial and spinal segments. He received treatment for multiple sclerosis but presented clinical worsening, and follow-up neuroimaging showed persistent contrast enhancement lesions and a cerebellar hematoma. Brain biopsy was performed and demonstrated inflammatory infiltrations in blood vessels. The patient received 6 monthly schedules of 5 g methylprednisolone and 1 g cyclophosphamide with clinical stabilization. DISCUSSION: Our patient presented a primary angiitis central nervous system according to the Birnbaum and Hellmann proposed criteria. This case reinforces the importance of advancing the differential diagnosis of patients that present red flags in brain neuroimaging. CONCLUSION: The presence of the micro/macrobleeds and persistent contrast enhancing lesions should raise the suspicion of vasculitis in the differential diagnosis of multiple sclerosis.

Asymptomatic MRI lesions in pediatric-onset AQP4-IgG positive NMOSD.

BACKGROUND AND PURPOSE: Around 5% of all Neuromyelitis Optica Spectrum Disorders (NMOSD) cases start before 18 years of age. Clinical and radiological manifestations of AQP4-IgG positive NMOSD were revised in 2015, and the importance of neuroimaging in the diagnosis is well recognized. Neuroimaging findings in pediatric-onset NMOSD were scarcely described, and longitudinal evaluation of NMOSD lesions was only accessed in a few adult-onset cohorts. METHODS: This study evaluated brain, spinal cord, and optic nerve MRI of sixteen pediatric-onset AQP4-IgG positive NMOSD through a qualitative evaluation of lesion evolution. Lesions were classified as symptomatic or asymptomatic in acute or chronic phase (> 30 days from last attack) MRI. RESULTS: Seventy MRI scans and 54 subsequent exams were evaluated. Most NMOSD lesions (74.5%) reduced, remained stable, or developed atrophy/cavitation. New brain lesions or enlargement of existing brain lesions were found in two patients (12.5%) without any clinical symptom and in five patients (31.2%) in the course of an attack from other topography (optic neuritis or acute myelitis). One patient (6.3%) presented an asymptomatic spinal cord lesion irrespective of clinical manifestation. No asymptomatic lesion was described in optic nerve MRI. In acute phase exams, longitudinally extensive transverse myelitis (13/19 vs 8/24; p = 0.033), cervical myelitis (15/19 vs 10/24, p = 0.028), lumbar myelitis (5/19 vs 0/24; p = 0.012), and a higher number of segments [median 8 (range 4-17) vs 3.5 (range 1-14); p = 0.003] were affected. CONCLUSIONS: Asymptomatic brain and spinal cord lesions can occur in pediatric-onset NMOSD, especially in the course of acute optic neuritis or myelitis. More longitudinal studies are necessary to guide recommendations on neuroimaging frequency in pediatric patients with AQP4-IgG NMOSD.

Nighttime Sleep Characteristics and White Matter Integrity in Young Adults.

Purpose: Sleep is essential for life and plays a key role for optimal physiology, brain functioning, and health. Evidence suggests a relation between sleep and cerebral white matter integrity. Human studies report that sleep duration shows a U-shaped association with brain functioning. We hypothesized that participants with longer or shorter sleep time in the nighttime period show altered microstructural white matter integrity. Participants and Methods: Seventy-three young adult participants were evaluated. Sleep-wake cycle parameters were assessed objectively using actigraphy. Diffusion tensor imaging studies were performed to assess white matter integrity using fractional anisotropy and mean, axial, and radial diffusivities. Relations between white matter microstructure indexes and sleep parameters were investigated through tract-based spatial statistics. Participants were grouped according to their nocturnal total sleep time: 27 in the Reference sleep group (6.5-8.0 h), 23 in the Short sleep group (<6.5 h) and 23 in the Long sleep group (>8.0 h). Results: Compared with the Reference sleep group, participants in the Long sleep group showed lower fractional anisotropy (p < 0.05) and higher radial diffusivity (p < 0.05) values in white matter tracts linked to sleep regulation (corona radiata, body of the corpus callosum, superior longitudinal fasciculus, and anterior thalamic radiation). Conclusion: This pattern of reduced fractional anisotropy and increased radial diffusivity in the Long sleep group indicates an association between sleep duration and lower integrity of myelin sheaths. Because myelin is continuously remodeled in the brain, nighttime sleep characteristics appear to be a key player for its quality and maintenance.

Innate immune cells and myelin profile in multiple sclerosis: a multi-tracer PET/MR study.

PURPOSE: Neuropathological studies have demonstrated distinct profiles of microglia activation and myelin injury among different multiple sclerosis (MS) phenotypes and disability stages. PET imaging using specific tracers may uncover the in vivo molecular pathology and broaden the understanding of the disease heterogeneity. METHODS: We used the 18-kDa translocator protein (TSPO) tracer (R)-[11C]PK11195 and [11C]PIB PET images acquired in a hybrid PET/MR 3 T system to characterize, respectively, the profile of innate immune cells and myelin content in 47 patients with MS compared to 18 healthy controls (HC). For the volume of interest (VOI)-based analysis of the dynamic data, (R)-[11C]PK11195 distribution volume (VT) was determined for each subject using a metabolite-corrected arterial plasma input function while [11C]PIB distribution volume ratio (DVR) was estimated using a reference region extracted by a supervised clustering algorithm. A voxel-based analysis was also performed using Statistical Parametric Mapping. Functional disability was evaluated by the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and Symbol Digit Modality Test (SDMT). RESULTS: In the VOI-based analysis, [11C]PIB DVR differed between patients and HC in the corpus callosum (P = 0.019) while no differences in (R)-[11C]PK11195 VT were observed in patients relative to HC. Furthermore, no correlations or associations were observed between both tracers within the VOI analyzed. In the voxel-based analysis, high (R)-[11C]PK11195 uptake was observed diffusively in the white matter (WM) when comparing the progressive phenotype and HC, and lower [11C]PIB uptake was observed in certain WM regions when comparing the relapsing-remitting phenotype and HC. None of the tracers were able to differentiate phenotypes at voxel or VOI level in our cohort. Linear regression models adjusted for age, sex, and phenotype demonstrated that higher EDSS was associated with an increased (R)-[11C]PK11195 VT and lower [11C]PIB DVR in corpus callosum (P = 0.001; P = 0.023), caudate (P = 0.015; P = 0.008), and total T2 lesion (P = 0.007; P = 0.012), while better cognitive scores in SDMT were associated with higher [11C]PIB DVR in the corpus callosum (P = 0.001), and lower (R)-[11C]PK11195 VT (P = 0.013). CONCLUSIONS: Widespread innate immune cells profile and marked loss of myelin in T2 lesions and regions close to the ventricles may occur independently and are associated with disability, in both WM and GM structures.

White matter microstructural damage in chronic ischemic stroke affecting the left inferior frontal gyrus: Association with cognitive functions.

Brain ischemia affects the integrity of local white matter and regions that are distant to the primary lesion location. In this study, we analyzed the patterns of white matter microstructural damage and the cognitive performance of 22 patients with left hemisphere stroke. Patients were divided in two groups: one with target lesion affecting the left inferior frontal gyrus (left inferior frontal gyrus, LIFG, n = 11) and the other without ischemic lesion in this region (non-left inferior frontal gyrus, NLIFG, n = 11). Each group was compared with 11 matched healthy controls. Tract-Based Spatial Statistics was used to assess differences in diffusion tensor indices between the groups and for the association of white matter structure with cognitive performance. When compared to Controls, the LIFG showed extensive intra- and interhemispheric disconnection, with surrogate markers for tissue loss with demyelination in the corpus callosum, and microstructural changes that are independent of gross tissue loss in the contralateral hemisphere. The NLIFG group presented discrete alterations in white matter from the ipsilateral hemisphere, with surrogate markers for tissue loss with axonal injury. When LIFG is compared to NLIFG, white matter abnormalities with no gross tissue loss were observed in the corpus callosum and in the contralateral hemisphere. In addition LIFG had worse performance on cognitive functions. In conclusion, our results identify different diffusion profiles for LIFG and NLIFG groups, suggesting more extensive and pronounced white matter damage in the commissural and interhemispheric connections in the LIFG group, in addition to more pronounced cognitive impairment.

The effect of lesion filling on brain network analysis in multiple sclerosis using structural magnetic resonance imaging.

BACKGROUND: Graph theoretical network analysis with structural magnetic resonance imaging (MRI) of multiple sclerosis (MS) patients can be used to assess subtle changes in brain networks. However, the presence of multiple focal brain lesions might impair the accuracy of automatic tissue segmentation methods, and hamper the performance of graph theoretical network analysis. Applying "lesion filling" by substituting the voxel intensities of a lesion with the voxel intensities of nearby voxels, thus creating an image devoid of lesions, might improve segmentation and graph theoretical network analysis. This study aims to determine if brain networks are different between MS subtypes and healthy controls (HC) and if the assessment of these differences is affected by lesion filling. METHODS: The study included 49 MS patients and 19 HC that underwent a T1w, and T2w-FLAIR MRI scan. Graph theoretical network analysis was performed from grey matter fractions extracted from the original T1w-images and T1w-images after lesion filling. RESULTS: Artefacts in lesion-filled T1w images correlated positively with total lesion volume (r = 0.84, p < 0.001) and had a major impact on grey matter segmentation accuracy. Differences in sensitivity for network alterations were observed between original T1w data and after application of lesion filling: graph theoretical network analysis obtained from lesion-filled T1w images produced more differences in network organization in MS patients. CONCLUSION: Lesion filling might reduce variability across subjects resulting in an increased detection rate of network alterations in MS, but also induces significant artefacts, and therefore should be applied cautiously especially in individuals with higher lesions loads.

Mechanisms of myelin repair, MRI techniques and therapeutic opportunities in multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). The remyelination process requires the activation, migration and differentiation of oligodendrocyte progenitor cells (OPC) in demyelinated areas. The metabolic dysfunction in chronic demyelinating lesions impairs the activation of OPCs, the myelin debris clearance by microglia decreases with age, along with diminished secretion of factors promoting OPC differentiation. Conventional magnetic resonance imaging (MRI) sequences have limited ability to differentiate unmyelinated and remyelinated lesions. Advanced MRI sequences based on magnetization transfer ratio (MTR), myelin water fraction (MWF) and diffusion tensor imaging (DTI) have been used to evaluate remyelination in clinical trials. More recently, the q-space myelin map (qMM) has been used on experimental and exploratory clinical studies. The improvement of myelin-specific MRI sequences with high reliability and standardization among centers will allow a more accurate evaluation of new therapies to improve remyelination. These new remyelination promoting treatments alone or in combination with current options may reduce the risk of long-term disability in MS.

Longitudinal assessment of magnetization transfer ratio, brain volume, and cognitive functions in diffuse axonal injury.

BACKGROUND: Diffuse axonal injury (DAI) is a frequent mechanism of traumatic brain injury (TBI) that triggers a sequence of parenchymal changes that progresses from focal axonal shear injuries up to inflammatory response and delayed axonal disconnection. OBJECTIVE: The main purpose of this study is to evaluate changes in the axonal/myelinic content and the brain volume up to 12 months after TBI and to correlate these changes with neuropsychological results. METHODS: Patients with DAI (n = 25) were scanned at three time points after trauma (2, 6, and 12 months), and the total brain volume (TBV), gray matter volume, and white matter volume (WMV) were calculated in each time point. The magnetization transfer ratio (MTR) for the total brain (TB MTR), gray matter (GM MTR), and white matter (WM MTR) was also quantified. In addition, Hopkins verbal learning test (HVLT), Trail Making Test (TMT), and Rey-Osterrieth Complex Figure test were performed at 6 and 12 months after the trauma. RESULTS: There was a significant reduction in the mean TBV, WMV, TB MTR, GM MTR, and WM MTR between time points 1 and 3 (p < .05). There was also a significant difference in HVLT-immediate, TMT-A, and TMT-B scores between time points 2 and 3. The MTR decline correlated more with the cognitive dysfunction than the volume reduction. CONCLUSION: A progressive axonal/myelinic rarefaction and volume loss were characterized, especially in the white matter (WM) up to 1 year after the trauma. Despite that, specific neuropsychological tests revealed that patients' episodic verbal memory, attention, and executive function improved during the study. The current findings may be valuable in developing long-term TBI rehabilitation management programs.

Reduced quality of life in a pediatric-onset Neuromyelitis optica spectrum disorders cohort.

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) is a severe condition associated with high disability and low quality of life (QoL) in adults. Since this evaluation had been rarely perfomed in children, this study aimed to describe QoL in pediatric-onset NMOSD with positive aquaporin4 antibody (AQP4-IgG) patients. METHODS: This was a cross-section evaluation of patients and parents' proxy QoL from individuals enrolled in a longitudinal cohort of AQP4-IgG positive NMOSD with onset ≤ 18 years of age. RESULTS: Eighteen patients were included, sixteen girls. The mean (SD) age at disease onset was 11.5 (3.6) years. Eleven of patients experienced disability during a mean (SD) of 8.3 (5.3) years of follow-up. NMOSD had impact in QoL in 10 patients, being associated with higher EDSS and poor academic performance at last follow-up. Results from the PedsQL inventory for 13 patients and 10 parents disclosed low QoL specially in emotional functioning. CONCLUSION: This study indicates impaired quality of life, high disability and high impact of the disease in daily life of adolescents and young adults with pediatric onset NMOSD.