Severe Tick-Borne Encephalitis (TBE) in a Patient with X-Linked Agammaglobulinemia; Treatment with TBE Virus IgG Positive Plasma, Clinical Outcome and T Cell Responses.

PURPOSE: A patient with X-linked agammaglobulinemia (XLA) and severe tick-borne encephalitis (TBE) was treated with TBE virus (TBEV) IgG positive plasma. The patient's clinical response, humoral and cellular immune responses were characterized pre- and post-infection. METHODS: ELISA and neutralisation assays were performed on sera and TBEV PCR assay on sera and cerebrospinal fluid. T cell assays were conducted on peripheral blood the patient and five healthy vaccinated controls. RESULTS: The patient was admitted to the hospital with headache and fever. He was not vaccinated against TBE but receiving subcutaneous IgG-replacement therapy (IGRT). TBEV IgG antibodies were low-level positive (due to scIGRT), but the TBEV IgM and TBEV neutralisation tests were negative. During hospitalisation his clinical condition deteriorated (Glasgow coma scale 3/15) and he was treated in the ICU with corticosteroids and external ventricular drainage. He was then treated with plasma containing TBEV IgG without apparent side effects. His symptoms improved within a few days and the TBEV neutralisation test converted to positive. Robust CD8+ T cell responses were observed at three and 18-months post-infection, in the absence of B cells. This was confirmed by tetramers specific for TBEV. CONCLUSION: TBEV IgG-positive plasma given to an XLA patient with TBE without evident adverse reactions may have contributed to a positive clinical outcome. Similar approaches could offer a promising foundation for researching therapeutic options for patients with humoral immunodeficiencies. Importantly, a robust CD8+ T cell response was observed after infection despite the lack of B cells and indicates that these patients can clear acute viral infections and could benefit from future vaccination programs.

A Genetic Risk Variant for Multiple Sclerosis Severity is Associated with Brain Atrophy.

The minor allele of the genetic variant rs10191329 in the DYSF-ZNF638 locus is associated with unfavorable long-term clinical outcomes in multiple sclerosis patients. We investigated if rs10191329 is associated with brain atrophy measured by magnetic resonance imaging in a discovery cohort of 748 and a replication cohort of 360 people with relapsing multiple sclerosis. We observed an association with 28% more brain atrophy per rs10191329*A allele. Our results encourage stratification for rs10191329 in clinical trials. Unraveling the underlying mechanisms may enhance our understanding of pathophysiology and identify treatment targets. ANN NEUROL 2023;94:1080-1085.

Phenotyping in vivo chronic inflammation in multiple sclerosis by combined 11C-PBR28 MR-PET and 7T susceptibility-weighted imaging.

BACKGROUND: 11C-PBR28 positron emission tomography (PET), targeting the translocator protein, and paramagnetic rim lesions (PRL) have emerged as promising imaging markers of MS chronic inflammation. No consensus on which is the optimal marker exists. OBJECTIVES: To investigate the ability of 11C-PBR28 PET and PRL assessment to identify chronic inflammation in white matter (WM) MS lesions and their relation to neurological impairment. METHODS: Based on 11C-PBR28 uptake, brain WM lesions from 30 MS patients were classified as PET active or inactive. The PRL presence was assessed on 7T phase reconstructions, T1/T2 ratio was calculated to measure WM microstructural integrity. RESULTS: Less than half (44%) of non-PRL WM lesions were active on 11C-PBR28 imaging either throughout the lesion (whole active) or at its periphery. PET peripherally active lesions and PRL did not differ in T1/T2 ratio and 11C-PBR28 uptake. A positive correlation was observed between PRL and active PET lesion count. Whole active PET lesion volume was the strongest predictor (ß = 0.97, p < 0.001) of increased Expanded Disability Status Scale scores. CONCLUSION: 11C-PBR28 imaging reveals more active WM lesions than 7T PRL assessment. Although PRL and PET active lesion counts are related, neurological disability is better explained by PET whole active lesion volume.

Misdiagnosis and underdiagnosis of multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: Diagnostic errors in multiple sclerosis (MS) impact patients and healthcare systems. OBJECTIVES: This study aimed to determine the prevalence of MS misdiagnosis and underdiagnosis, time delay in reaching a correct diagnosis and potential impact of sex. METHODS: Systematic review and meta-analysis on MS diagnostic errors. RESULTS: Out of 3910 studies, we included 62 for a qualitative synthesis and 24 for meta-analyses. Frequency of misdiagnosis (incorrect assignment of an MS diagnosis) ranged from 5% to 41%, with a pooled proportion based on six studies of 15% (95% CI: 9%-26%, n = 1621). The delay to rectify a misdiagnosis ranged from 0.3 to 15.9 years. Conversely, underdiagnosis (unrecognized diagnosis of MS) ranged from 3% to 58%, with a pooled proportion in four studies of 36% (95% CI: 20%-55%, n = 728). Pooling seven studies comprising 2851 individuals suggested a diagnostic delay to establish a correct MS diagnosis of 17.3 months (95% CI: 11.9-22.7) in patients underdiagnosed. In a meta-analysis of five studies, women were 2.1 times more likely to be misdiagnosed with MS compared to men (odds ratio, 95% CI: 1.53-2.86). CONCLUSION: This study provides summary-level evidence for the high prevalence of MS misdiagnosis and underdiagnosis. Future studies are needed to understand the causes of these diagnostic challenges in MS care.

Clinical and neuroimaging phenotypes of autoimmune glial fibrillary acidic protein astrocytopathy: A systematic review and meta-analysis.

OBJECTIVE: This study was undertaken to provide a comprehensive review of neuroimaging characteristics and corresponding clinical phenotypes of autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A), a rare but severe neuroinflammatory disorder, to facilitate early diagnosis and appropriate treatment. METHODS: A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis)-conforming systematic review and meta-analysis was performed on all available data from January 2016 to June 2023. Clinical and neuroimaging phenotypes were extracted for both adult and paediatric forms. RESULTS: A total of 93 studies with 681 cases (55% males; median age = 46, range = 1-103 years) were included. Of these, 13 studies with a total of 535 cases were eligible for the meta-analysis. Clinically, GFAP-A was often preceded by a viral prodromal state (45% of cases) and manifested as meningitis, encephalitis, and/or myelitis. The most common symptoms were headache, fever, and movement disturbances. Coexisting autoantibodies (45%) and neoplasms (18%) were relatively frequent. Corticosteroid treatment resulted in partial/complete remission in a majority of cases (83%). Neuroimaging often revealed T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities (74%) as well as perivascular (45%) and/or leptomeningeal (30%) enhancement. Spinal cord abnormalities were also frequent (49%), most commonly manifesting as longitudinally extensive myelitis. There were 88 paediatric cases; they had less prominent neuroimaging findings with lower frequencies of both T2/FLAIR hyperintensities (38%) and contrast enhancement (19%). CONCLUSIONS: This systematic review and meta-analysis provide high-level evidence for clinical and imaging phenotypes of GFAP-A, which will benefit the identification and clinical workup of suspected cases. Differential diagnostic cues to distinguish GFAP-A from common clinical and imaging mimics are provided as well as suitable magnetic resonance imaging protocol recommendations.

Towards more realistic measures of accessibility to emergency departments in Sweden.

BACKGROUND: Assuring that emergency health care (EHC) is accessible is a key objective for health care planners. Conventional accessibility analysis commonly relies on resident population data. However, the allocation of resources based on stationary population data may lead to erroneous assumptions of population accessibility to EHC. METHOD: Therefore, in this paper, we calculate population accessibility to emergency departments in Sweden with a geographical information system based network analysis. Utilizing static population data and dynamic population data, we investigate spatiotemporal patterns of how static population data over- or underestimates population sizes derived from temporally dynamic population data. RESULTS: Our findings show that conventional measures of population accessibility tend to underestimate population sizes particularly in rural areas and in smaller ED's catchment areas compared to urban, larger ED's-especially during vacation time in the summer. CONCLUSIONS: Planning based on static population data may thus lead to inequitable distributions of resources. This study is motivated in light of the ongoing centralization of ED's in Sweden, which largely depends on population sizes in ED's catchment areas.

Lung perfusion disturbances in nonhospitalized post-COVID with dyspnea-A magnetic resonance imaging feasibility study.

BACKGROUND: Dyspnea is common after COVID-19. Though the underlying mechanisms are largely unknown, lung perfusion abnormalities could contribute to lingering dyspnea. OBJECTIVES: To detect pulmonary perfusion disturbances in nonhospitalized individuals with the post-COVID condition and persistent dyspnea 4-13 months after the disease onset. METHODS: Individuals with dyspnea and matched healthy controls were recruited for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), a 6-min walk test, and an assessment of dyspnea. The DCE-MRI was quantified using two parametric values: mean time to peak (TTP) and TTP ratio, reflecting the total lung perfusion resistance and the fraction of lung with delayed perfusion, respectively. RESULTS: Twenty-eight persons with persistent dyspnea (mean age 46.5 ± 8.0 years, 75% women) and 22 controls (mean age 44.1 ± 10.8 years, 73% women) were included. There was no systematic sex difference in dyspnea. The post-COVID group had no focal perfusion deficits but had higher mean pulmonary TTP (0.43 ± 0.04 vs. 0.41 ± 0.03, p = 0.011) and TTP ratio (0.096 ± 0.052 vs. 0.068 ± 0.027, p = 0.032). Post-COVID males had the highest mean TTP of 0.47 ± 0.02 and TTP ratio of 0.160 ± 0.039 compared to male controls and post-COVID females (p = 0.001 and p < 0.001, respectively). Correlations between dyspnea and perfusion parameters were demonstrated in males (r = 0.83, p < 0.001 for mean TTP; r = 0.76, p = 0.003 for TTP ratio), but not in females. CONCLUSIONS: DCE-MRI demonstrated late contrast bolus arrival in males with post-COVID dyspnea, suggestive of primary vascular lesions or secondary effects of hypoxic vasoconstriction. Since this effect was not regularly observed in female patients, our findings suggest sex differences in the mechanisms underlying post-COVID dyspnea, which warrants further investigation in dedicated trials.

Neuroimaging phenotypes of CSF1R-related leukoencephalopathy: Systematic review, meta-analysis, and imaging recommendations.

Colony-stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy is a rare but fatal microgliopathy. The diagnosis is often delayed due to multifaceted symptoms that can mimic several other neurological disorders. Imaging provides diagnostic clues that help identify cases. The objective of this study was to integrate the literature on neuroimaging phenotypes of CSF1R-related leukoencephalopathy. A systematic review and meta-analysis were performed for neuroimaging findings of CSF1R-related leukoencephalopathy via PubMed, Web of Science, and Embase on 25 August 2021. The search included cases with confirmed CSF1R mutations reported under the previous terms hereditary diffuse leukoencephalopathy with spheroids, pigmentary orthochromatic leukodystrophy, and adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. In 78 studies providing neuroimaging data, 195 cases were identified carrying CSF1R mutations in 14 exons and five introns. Women had a statistically significant earlier age of onset (p = 0.041, 40 vs 43 years). Mean delay between symptom onset and neuroimaging was 2.3 years. Main magnetic resonance imaging (MRI) findings were frontoparietal white matter lesions, callosal thinning, and foci of restricted diffusion. The hallmark computed tomography (CT) finding was white matter calcifications. Widespread cerebral hypometabolism and hypoperfusion were reported using positron emission tomography and single-photon emission computed tomography. In conclusion, CSF1R-related leukoencephalopathy is associated with progressive white matter lesions and brain atrophy that can resemble other neurodegenerative/-inflammatory disorders. However, long-lasting diffusion restriction and parenchymal calcifications are more specific findings that can aid the differential diagnosis. Native brain CT and brain MRI (with and without a contrast agent) are recommended with proposed protocols and pictorial examples are provided.

Four Swedish cases of CSF1R-related leukoencephalopathy: Visualization of clinical phenotypes.

Colony stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy is a rare, genetic disease caused by heterozygous mutations in the CSF1R gene with rapidly progressive neurodegeneration, behavioral, cognitive, motor disturbances. OBJECTIVE: To describe four cases of CSF1R-related leukoencephalopathy from three families with two different pathogenic mutations in the tyrosine kinase domain of CSF1R and to develop an integrated presentation of inter-individual diversity of clinical presentations. METHODS: This is an observational study of a case series. Patients diagnosed with CSF1R encephalopathy were evaluated with standardized functional estimation scores and subject to analysis of cerebrospinal fluid biomarkers. Brain computed tomography (CT) and magnetic resonance imaging (MRI) were evaluated. We performed a functional phosphorylation assay to confirm the dysfunction of mutated CSF1R protein. RESULTS: Two heterozygous missense mutations in the CSF1R gene were identified, c.2344C>T; p.Arg777Trp and c.2329C>T; p.Arg782Cys. A phosphorylation assay in vitro showed markedly reduced autophosphorylation in cells expressing mutations. According to ACMG criteria, both mutations were pathogenic. A radiological investigation revealed typical white matter lesions in all cases. There was inter-individual diversity in the loss of cognitive, motor-neuronal, and extrapyramidal functions. CONCLUSIONS: Including the present cases, currently three CSF1R mutations are known in Sweden. We present a visualization tool to describe the clinical diversity, with potential use for longitudinal follow-up for this and other leukoencephalopathies.

The Karolinska NeuroCOVID study protocol: Neurocognitive impairment, biomarkers and advanced imaging in critical care survivors.

BACKGROUND: This is the study plan of the Karolinska NeuroCOVID study, a study of neurocognitive impairment after severe COVID-19, relating post-intensive care unit (ICU) cognitive and neurological deficits to biofluid markers and MRI. The COVID-19 pandemic has posed enormous health challenges to individuals and health-care systems worldwide. An emerging feature of severe COVID-19 is that of temporary and extended neurocognitive impairment, exhibiting a myriad of symptoms and signs. The causes of this symptomatology have not yet been fully elucidated. METHODS: In this study, we aim to investigate patients treated for severe COVID-19 in the ICU, as to describe and relate serum-, plasma- and cerebrospinal fluid-borne molecular and cellular biomarkers of immune activity, coagulopathy, cerebral damage, neuronal inflammation, and degeneration, to the temporal development of structural and functional changes within the brain as evident by serial MRI and extensive cognitive assessments at 3-12 months after ICU discharge. RESULTS: To date, we have performed 51 3-month follow-up MRIs in the ICU survivors. Of these, two patients (~4%) have had incidental findings on brain MRI findings requiring activation of the Incidental Findings Management Plan. Furthermore, the neuropsychological and neurological examinations have so far revealed varying and mixed patterns. Several patients expressed cognitive and/or mental concerns and fatigue, complaints closely related to brain fog. CONCLUSION: The study goal is to gain a better understanding of the pathological mechanisms and neurological consequences of this new disease, with a special emphasis on neurodegenerative and neuroinflammatory processes, in order to identify targets of intervention and rehabilitation.

Validation of Rapid Magnetic Resonance Myelin Imaging in Multiple Sclerosis.

OBJECTIVE: Magnetic resonance imaging (MRI) is essential for multiple sclerosis diagnostics but is conventionally not specific to demyelination. Myelin imaging is often hampered by long scanning times, complex postprocessing, or lack of clinical approval. This study aimed to assess the specificity, robustness, and clinical value of Rapid Estimation of Myelin for Diagnostic Imaging, a new myelin imaging technique based on time-efficient simultaneous T1 /T2 relaxometry and proton density mapping in multiple sclerosis. METHODS: Rapid myelin imaging was applied using 3T MRI ex vivo in 3 multiple sclerosis brain samples and in vivo in a prospective cohort of 71 multiple sclerosis patients and 21 age/sex-matched healthy controls, with scan-rescan repeatability in a subcohort. Disability in patients was assessed by the Expanded Disability Status Scale and the Symbol Digit Modalities Test at baseline and 2-year follow-up. RESULTS: Rapid myelin imaging correlated with myelin-related stains (proteolipid protein immunostaining and Luxol fast blue) and demonstrated good precision. Multiple sclerosis patients had, relative to controls, lower normalized whole-brain and normal-appearing white matter myelin fractions, which correlated with baseline cognitive and physical disability. Longitudinally, these myelin fractions correlated with follow-up physical disability, even with correction for baseline disability. INTERPRETATION: Rapid Estimation of Myelin for Diagnostic Imaging provides robust myelin quantification that detects diffuse demyelination in normal-appearing tissue in multiple sclerosis, which is associated with both cognitive and clinical disability. Because the technique is fast, with automatic postprocessing and US Food and Drug Administration/CE clinical approval, it can be a clinically feasible biomarker that may be suitable to monitor myelin dynamics and evaluate treatments aiming at remyelination. ANN NEUROL 2020;87:710-724.

7 T imaging reveals a gradient in spinal cord lesion distribution in multiple sclerosis.

We used 7 T MRI to: (i) characterize the grey and white matter pathology in the cervical spinal cord of patients with early relapsing-remitting and secondary progressive multiple sclerosis; (ii) assess the spinal cord lesion spatial distribution and the hypothesis of an outside-in pathological process possibly driven by CSF-mediated immune cytotoxic factors; and (iii) evaluate the association of spinal cord pathology with brain burden and its contribution to neurological disability. We prospectively recruited 20 relapsing-remitting, 15 secondary progressive multiple sclerosis participants and 11 age-matched healthy control subjects to undergo 7 T imaging of the cervical spinal cord and brain as well as conventional 3 T brain acquisition. Cervical spinal cord imaging at 7 T was used to segment grey and white matter, including lesions therein. Brain imaging at 7 T was used to segment cortical and white matter lesions and 3 T imaging for cortical thickness estimation. Cervical spinal cord lesions were mapped voxel-wise as a function of distance from the inner central canal CSF pool to the outer subpial surface. Similarly, brain white matter lesions were mapped voxel-wise as a function of distance from the ventricular system. Subjects with relapsing-remitting multiple sclerosis showed a greater predominance of spinal cord lesions nearer the outer subpial surface compared to secondary progressive cases. Inversely, secondary progressive participants presented with more centrally located lesions. Within the brain, there was a strong gradient of lesion formation nearest the ventricular system that was most evident in participants with secondary progressive multiple sclerosis. Lesion fractions within the spinal cord grey and white matter were related to the lesion fraction in cerebral white matter. Cortical thinning was the primary determinant of the Expanded Disability Status Scale, white matter lesion fractions in the spinal cord and brain of the 9-Hole Peg Test and cortical thickness and spinal cord grey matter cross-sectional area of the Timed 25-Foot Walk. Spinal cord lesions were localized nearest the subpial surfaces for those with relapsing-remitting and the central canal CSF surface in progressive disease, possibly implying CSF-mediated pathogenic mechanisms in lesion development that may differ between multiple sclerosis subtypes. These findings show that spinal cord lesions involve both grey and white matter from the early multiple sclerosis stages and occur mostly independent from brain pathology. Despite the prevalence of cervical spinal cord lesions and atrophy, brain pathology seems more strongly related to physical disability as measured by the Expanded Disability Status Scale.

Multiple sclerosis lesions in motor tracts from brain to cervical cord: spatial distribution and correlation with disability.

Despite important efforts to solve the clinico-radiological paradox, correlation between lesion load and physical disability in patients with multiple sclerosis remains modest. One hypothesis could be that lesion location in corticospinal tracts plays a key role in explaining motor impairment. In this study, we describe the distribution of lesions along the corticospinal tracts from the cortex to the cervical spinal cord in patients with various disease phenotypes and disability status. We also assess the link between lesion load and location within corticospinal tracts, and disability at baseline and 2-year follow-up. We retrospectively included 290 patients (22 clinically isolated syndrome, 198 relapsing remitting, 39 secondary progressive, 31 primary progressive multiple sclerosis) from eight sites. Lesions were segmented on both brain (T2-FLAIR or T2-weighted) and cervical (axial T2- or T2*-weighted) MRI scans. Data were processed using an automated and publicly available pipeline. Brain, brainstem and spinal cord portions of the corticospinal tracts were identified using probabilistic atlases to measure the lesion volume fraction. Lesion frequency maps were produced for each phenotype and disability scores assessed with Expanded Disability Status Scale score and pyramidal functional system score. Results show that lesions were not homogeneously distributed along the corticospinal tracts, with the highest lesion frequency in the corona radiata and between C2 and C4 vertebral levels. The lesion volume fraction in the corticospinal tracts was higher in secondary and primary progressive patients (mean = 3.6 ± 2.7% and 2.9 ± 2.4%), compared to relapsing-remitting patients (1.6 ± 2.1%, both P < 0.0001). Voxel-wise analyses confirmed that lesion frequency was higher in progressive compared to relapsing-remitting patients, with significant bilateral clusters in the spinal cord corticospinal tracts (P < 0.01). The baseline Expanded Disability Status Scale score was associated with lesion volume fraction within the brain (r = 0.31, P < 0.0001), brainstem (r = 0.45, P < 0.0001) and spinal cord (r = 0.57, P < 0.0001) corticospinal tracts. The spinal cord corticospinal tracts lesion volume fraction remained the strongest factor in the multiple linear regression model, independently from cord atrophy. Baseline spinal cord corticospinal tracts lesion volume fraction was also associated with disability progression at 2-year follow-up (P = 0.003). Our results suggest a cumulative effect of lesions within the corticospinal tracts along the brain, brainstem and spinal cord portions to explain physical disability in multiple sclerosis patients, with a predominant impact of intramedullary lesions.

Nervous System Involvement in Coronavirus Disease 2019: Results from a Retrospective Consecutive Neuroimaging Cohort.

Background Neurologic complications in coronavirus disease 2019 (COVID-19) have been described, but the understanding of their pathophysiologic causes and neuroanatomical correlates remains limited. Purpose To report on the frequency and type of neuroradiological findings in COVID-19. Materials and Methods In this retrospective study, all consecutive adult hospitalized patients with polymerase chain reaction positivity for severe acute respiratory syndrome coronavirus 2 and who underwent neuroimaging at Karolinska University Hospital between March 2 and May 24, 2020, were included. All examinations were systematically re-evaluated by 12 readers. Summary descriptive statistics were calculated. Results A total of 185 patients with COVID-19 (62 years ± 14 [standard deviation]; 138 men) underwent neuroimaging. In total, 222 brain CT, 47 brain MRI, and seven spinal MRI examinations were performed. Intra-axial susceptibility abnormalities were the most common finding (29 of 39; 74%, 95% CI: 58, 87) in patients who underwent brain MRI, often with an ovoid shape suggestive of microvascular pathology and with a predilection for the corpus callosum (23 of 39; 59%; 95% CI: 42, 74) and juxtacortical areas (14 of 39; 36%; 95% CI: 21, 53). Ischemic and macrohemorrhagic manifestations were also observed, but vascular imaging did not demonstrate overt abnormalities. Dynamic susceptibility contrast perfusion MRI in 19 patients did not reveal consistent asymmetries between hemispheres or regions. Many patients (18 of 41; 44%; 95% CI: 28, 60) had leukoencephalopathy and one patient had a cytotoxic lesion of the corpus callosum. Other findings included olfactory bulb signal abnormalities (seven of 37; 19%), prominent optic nerve subarachnoid spaces (20 of 36; 56%), and enhancement of the parenchyma (three of 20; 15%), leptomeninges (three of 20; 15%), cranial nerves (two of 20; 10%), and spinal nerves (two of four; 50%). At MRI follow-up, regression of leukoencephalopathy and progressive leptomeningeal enhancement was observed in one patient each, respectively, which is suggestive of dynamic processes. Conclusion Patients with coronavirus disease 2019 had a wide spectrum of vascular and inflammatory involvement of both the central and peripheral nervous system. © RSNA, 2020 Online supplemental material is available for this article.

Rare variants in dynein heavy chain genes in two individuals with situs inversus and developmental dyslexia: a case report.

BACKGROUND: Developmental dyslexia (DD) is a neurodevelopmental learning disorder with high heritability. A number of candidate susceptibility genes have been identified, some of which are linked to the function of the cilium, an organelle regulating left-right asymmetry development in the embryo. Furthermore, it has been suggested that disrupted left-right asymmetry of the brain may play a role in neurodevelopmental disorders such as DD. However, it is unknown whether there is a common genetic cause to DD and laterality defects or ciliopathies. CASE PRESENTATION: Here, we studied two individuals with co-occurring situs inversus (SI) and DD using whole genome sequencing to identify genetic variants of importance for DD and SI. Individual 1 had primary ciliary dyskinesia (PCD), a rare, autosomal recessive disorder with oto-sino-pulmonary phenotype and SI. We identified two rare nonsynonymous variants in the dynein axonemal heavy chain 5 gene (DNAH5): a previously reported variant c.7502G > C; p.(R2501P), and a novel variant c.12043 T > G; p.(Y4015D). Both variants are predicted to be damaging. Ultrastructural analysis of the cilia revealed a lack of outer dynein arms and normal inner dynein arms. MRI of the brain revealed no significant abnormalities. Individual 2 had non-syndromic SI and DD. In individual 2, one rare variant (c.9110A > G;p.(H3037R)) in the dynein axonemal heavy chain 11 gene (DNAH11), coding for another component of the outer dynein arm, was identified. CONCLUSIONS: We identified the likely genetic cause of SI and PCD in one individual, and a possibly significant heterozygosity in the other, both involving dynein genes. Given the present evidence, it is unclear if the identified variants also predispose to DD and further studies into the association between laterality, ciliopathies and DD are needed.

Rituximab treatment for multiple sclerosis.

Rituximab, a chimeric anti-CD20-antibody, attracts increasing attention as a treatment option for multiple sclerosis (MS). Apart from smaller controlled trials, an increasing number of studies in real-world populations indicate high efficacy based on clinical and neuroradiological outcomes for rituximab in relapsing-remitting MS patients. Additional evidence also demonstrates efficacy of rituximab with treatment of progressive MS phenotypes. In this topical review, we summarize and discuss current evidence on mechanisms of action, efficacy, safety, tolerance and other clinical aspects of rituximab in the treatment of MS. Finally, we will highlight current knowledge gaps and the need for comparative studies with other disease-modifying therapies in MS.

Spatial distribution of multiple sclerosis lesions in the cervical spinal cord.

Spinal cord lesions detected on MRI hold important diagnostic and prognostic value for multiple sclerosis. Previous attempts to correlate lesion burden with clinical status have had limited success, however, suggesting that lesion location may be a contributor. Our aim was to explore the spatial distribution of multiple sclerosis lesions in the cervical spinal cord, with respect to clinical status. We included 642 suspected or confirmed multiple sclerosis patients (31 clinically isolated syndrome, and 416 relapsing-remitting, 84 secondary progressive, and 73 primary progressive multiple sclerosis) from 13 clinical sites. Cervical spine lesions were manually delineated on T2- and T2*-weighted axial and sagittal MRI scans acquired at 3 or 7 T. With an automatic publicly-available analysis pipeline we produced voxelwise lesion frequency maps to identify predilection sites in various patient groups characterized by clinical subtype, Expanded Disability Status Scale score and disease duration. We also measured absolute and normalized lesion volumes in several regions of interest using an atlas-based approach, and evaluated differences within and between groups. The lateral funiculi were more frequently affected by lesions in progressive subtypes than in relapsing in voxelwise analysis (P < 0.001), which was further confirmed by absolute and normalized lesion volumes (P < 0.01). The central cord area was more often affected by lesions in primary progressive than relapse-remitting patients (P < 0.001). Between white and grey matter, the absolute lesion volume in the white matter was greater than in the grey matter in all phenotypes (P < 0.001); however when normalizing by each region, normalized lesion volumes were comparable between white and grey matter in primary progressive patients. Lesions appearing in the lateral funiculi and central cord area were significantly correlated with Expanded Disability Status Scale score (P < 0.001). High lesion frequencies were observed in patients with a more aggressive disease course, rather than long disease duration. Lesions located in the lateral funiculi and central cord area of the cervical spine may influence clinical status in multiple sclerosis. This work shows the added value of cervical spine lesions, and provides an avenue for evaluating the distribution of spinal cord lesions in various patient groups.

Brain Atrophy Subtypes and the ATN Classification Scheme in Alzheimer's Disease.

INTRODUCTION: We investigated the association between atrophy subtypes of Alzheimer's disease (AD), the ATN classification scheme, and key demographic and clinical factors in 2 cohorts with different source characteristics (a highly selective research-oriented cohort, the Alzheimer's Disease Neuroimaging Initiative [ADNI]; and a naturalistic heterogeneous clinically oriented cohort, Karolinska Imaging Dementia Study [KIDS]). METHODS: A total of 382 AD patients were included. Factorial analysis of mixed data was used to investigate associations between AD subtypes based on brain atrophy patterns, ATN profiles based on cerebrospinal fluid biomarkers, and age, sex, Mini Mental State Examination (MMSE), cerebrovascular disease (burden of white matter signal abnormalities, WMSAs), and APOE genotype. RESULTS: Older patients with high WMSA burden, belonging to the typical AD subtype and showing A+T+N+ or A+T+N- profiles clustered together and were mainly from ADNI. Younger patients with low WMSA burden, limbic-predominant or minimal atrophy AD subtypes, and A+T-N- or A+T-N+ profiles clustered together and were mainly from KIDS. APOE ε4 carriers more frequently showed the A+T-N- and A+T+N- profiles. CONCLUSIONS: Our findings align with the recent framework for biological subtypes of AD: the combination of risk factors, protective factors, and brain pathologies determines belonging of AD patients to distinct subtypes.

Automatic segmentation of the spinal cord and intramedullary multiple sclerosis lesions with convolutional neural networks.

The spinal cord is frequently affected by atrophy and/or lesions in multiple sclerosis (MS) patients. Segmentation of the spinal cord and lesions from MRI data provides measures of damage, which are key criteria for the diagnosis, prognosis, and longitudinal monitoring in MS. Automating this operation eliminates inter-rater variability and increases the efficiency of large-throughput analysis pipelines. Robust and reliable segmentation across multi-site spinal cord data is challenging because of the large variability related to acquisition parameters and image artifacts. In particular, a precise delineation of lesions is hindered by a broad heterogeneity of lesion contrast, size, location, and shape. The goal of this study was to develop a fully-automatic framework - robust to variability in both image parameters and clinical condition - for segmentation of the spinal cord and intramedullary MS lesions from conventional MRI data of MS and non-MS cases. Scans of 1042 subjects (459 healthy controls, 471 MS patients, and 112 with other spinal pathologies) were included in this multi-site study (n = 30). Data spanned three contrasts (T1-, T2-, and T2∗-weighted) for a total of 1943 vol and featured large heterogeneity in terms of resolution, orientation, coverage, and clinical conditions. The proposed cord and lesion automatic segmentation approach is based on a sequence of two Convolutional Neural Networks (CNNs). To deal with the very small proportion of spinal cord and/or lesion voxels compared to the rest of the volume, a first CNN with 2D dilated convolutions detects the spinal cord centerline, followed by a second CNN with 3D convolutions that segments the spinal cord and/or lesions. CNNs were trained independently with the Dice loss. When compared against manual segmentation, our CNN-based approach showed a median Dice of 95% vs. 88% for PropSeg (p ≤ 0.05), a state-of-the-art spinal cord segmentation method. Regarding lesion segmentation on MS data, our framework provided a Dice of 60%, a relative volume difference of -15%, and a lesion-wise detection sensitivity and precision of 83% and 77%, respectively. In this study, we introduce a robust method to segment the spinal cord and intramedullary MS lesions on a variety of MRI contrasts. The proposed framework is open-source and readily available in the Spinal Cord Toolbox.

Longitudinal Characterization of Cortical Lesion Development and Evolution in Multiple Sclerosis with 7.0-T MRI.

Background Cortical lesions develop early in multiple sclerosis (MS) and play a major role in disease progression. MRI at 7.0 T shows high sensitivity for detection of cortical lesions as well as better spatial resolution and signal-to-noise ratio compared with lower field strengths. Purpose To longitudinally characterize (a) the development and evolution of cortical lesions in multiple sclerosis across the cortical width, sulci, and gyri; (b) their relation with white matter lesion accrual; and (c) the contribution of 7.0-T cortical and white matter lesion load and cortical thickness to neurologic disability. Materials and Methods Twenty participants with relapsing-remitting MS and 13 with secondary progressive MS, along with 10 age-matched healthy controls, were prospectively recruited from 2010 to 2016 to acquire, in two imaging sessions (mean interval, 1.5 years), 7.0-T MRI T2*-weighted gradient-echo images (0.33 × 0.33 × 1.0 mm3) for cortical and white matter lesion segmentation and 3.0-T T1-weighted images for cortical surface reconstruction and cortical thickness estimation. Cortical lesions were sampled through the cortex to quantify cortical lesion distribution. The Expanded Disability Status Scale (EDSS) was used to assess neurologic disability. Nonparametric statistics assessed differences between and within groups in MRI metrics of cortical and white matter lesion burden; regression analysis explored associations of disability with MRI metrics. Results Twenty-five of 31 (81%) participants developed new cortical lesions per year (intracortical, 1.3 ± 1.7 vs leukocortical, 0.7 ± 1.9; P = .04), surpassing white matter lesion accrual (cortical, 2.0 ± 2.8 vs white matter, 0.7 ± 0.6; P = .01). In contrast to white matter lesions, cortical lesion accrual was greater in participants with secondary progressive MS than with relapsing-remitting MS (3.6 lesions/year ± 4.2 vs 1.1 lesions/year ± 0.9, respectively; P = .03) and preferentially localized in sulci. Total cortical lesion volume independently predicted baseline EDSS (ß = 1.5, P < .001) and EDSS changes at follow-up (ß = 0.5, P = .003). Conclusion Cortical lesions predominantly develop intracortically and within sulci, suggesting an inflammatory cerebrospinal fluid-mediated lesion pathogenesis. Cortical lesion accumulation was prominent at 7.0 T and independently predicted neurologic disability progression. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Filippi and Rocca in this issue.