Publications by authors named "Christian Cordano"

42 Publications

Distinctive waves of innate immune response in the retina in experimental autoimmune encephalomyelitis.

JCI Insight 2021 Jun 8;6(11). Epub 2021 Jun 8.

Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, California, USA.

Neurodegeneration mediates neurological disability in inflammatory demyelinating diseases of the CNS. The role of innate immune cells in mediating this damage has remained controversial with evidence for destructive and protective effects. This has complicated efforts to develop treatment. The time sequence and dynamic evolution of the opposing functions are especially unclear. Given limits of in vivo monitoring in human diseases such as multiple sclerosis (MS), animal models are warranted to investigate the association and timing of innate immune activation with neurodegeneration. Using noninvasive in vivo retinal imaging of experimental autoimmune encephalitis (EAE) in CX3CR1GFP/+-knock-in mice followed by transcriptional profiling, we are able to show 2 distinct waves separated by a marked reduction in the number of innate immune cells and change in cell morphology. The first wave is characterized by an inflammatory phagocytic phenotype preceding the onset of EAE, whereas the second wave is characterized by a regulatory, antiinflammatory phenotype during the chronic stage. Additionally, the magnitude of the first wave is associated with neuronal loss. Two transcripts identified - growth arrest-specific protein 6 (GAS6) and suppressor of cytokine signaling 3 (SOCS3) - might be promising targets for enhancing protective effects of microglia in the chronic phase after initial injury.
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http://dx.doi.org/10.1172/jci.insight.149228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262300PMC
June 2021

Multiple Sclerosis Is Rare in Epstein-Barr Virus-Seronegative Children with Central Nervous System Inflammatory Demyelination.

Ann Neurol 2021 06 24;89(6):1234-1239. Epub 2021 Mar 24.

Department of Neurology, University of California, San Francisco, San Francisco, CA.

Although Epstein-Barr virus (EBV) is hypothesized to be a prerequisite for multiple sclerosis (MS), up to 15% of children with a diagnosis of MS were reported to be EBV-seronegative. When re-evaluating 25 EBV-seronegative children out of 189 pediatric patients with a diagnosis of clinically isolated syndrome/MS, we found anti-myelin oligodendrocyte glycoprotein (MOG) antibody in 11 of 25 (44%) EBV-seronegative but only 9 of 164 (5.5%, p < 0.001) EBV-seropositive patients. After critical review, MS remained a plausible diagnosis in only 4 of 14 EBV-seronegative/MOG antibody-negative patients. In children with an MS-like presentation, EBV seronegativity should alert clinicians to consider diagnoses other than MS, especially MOG-antibody disease. ANN NEUROL 2021;89:1234-1239.
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http://dx.doi.org/10.1002/ana.26062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244760PMC
June 2021

Multiple sclerosis and COVID-19: How could therapeutic scenarios change during the pandemic?

J Med Virol 2021 04 22;93(4):1847-1849. Epub 2021 Jan 22.

Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, California, USA.

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http://dx.doi.org/10.1002/jmv.26796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014825PMC
April 2021

Safety and efficacy of amantadine, modafinil, and methylphenidate for fatigue in multiple sclerosis: a randomised, placebo-controlled, crossover, double-blind trial.

Lancet Neurol 2021 01 23;20(1):38-48. Epub 2020 Nov 23.

Department of Neurology, University of California San Francisco, San Francisco, CA, USA.

Background: Methylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis; however, the evidence supporting their efficacy is sparse and conflicting. Our goal was to compare the efficacy of these three medications with each other and placebo in patients with multiple sclerosis fatigue.

Methods: In this randomised, placebo-controlled, four-sequence, four-period, crossover, double-blind trial, patients with multiple sclerosis who reported fatigue and had a Modified Fatigue Impact Scale (MFIS) score of more than 33 were recruited at two academic multiple sclerosis centres in the USA. Participants received oral amantadine (up to 100 mg twice daily), modafinil (up to 100 mg twice daily), methylphenidate (up to 10 mg twice daily), or placebo, each given for up to 6 weeks. All patients were intended to receive all four study medications, in turn, in one of four different sequences with 2-week washout periods between medications. A biostatistician prepared a concealed allocation schedule, stratified by site, randomly assigning a sequence of medications in approximately a 1:1:1:1 ratio, in blocks of eight, to a consecutive series of numbers. The statistician and pharmacists had no role in assessing the participants or collecting data, and the participants, caregivers, and assessors were masked to allocation. The primary outcome measure was the MFIS measured while taking the highest tolerated dose at week 5 of each medication period, analysed by use of a linear mixed-effect regression model. This trial is registered with ClinicalTrials.gov, NCT03185065 and is closed.

Findings: Between Oct 4, 2017, and Feb 27, 2019, of 169 patients screened, 141 patients were enrolled and randomly assigned to one of four medication administration sequences: 35 (25%) patients to the amantadine, placebo, modafinil, and methylphenidate sequence; 34 (24%) patients to the placebo, methylphenidate, amantadine, and modafinil sequence; 35 (25%) patients to the modafinil, amantadine, methylphenidate, and placebo sequence; and 37 (26%) patients to the methylphenidate, modafinil, placebo, and amantadine sequence. Data from 136 participants were available for the intention-to-treat analysis of the primary outcome. The estimated mean values of MFIS total scores at baseline and the maximal tolerated dose were as follows: 51·3 (95% CI 49·0-53·6) at baseline, 40·6 (38·2-43·1) with placebo, 41·3 (38·8-43·7) with amantadine, 39·0 (36·6-41·4) with modafinil, and 38·6 (36·2-41·0) with methylphenidate (p=0·20 for the overall medication effect in the linear mixed-effect regression model). As compared with placebo (38 [31%] of 124 patients), higher proportions of participants reported adverse events while taking amantadine (49 [39%] of 127 patients), modafinil (50 [40%] of 125 patients), and methylphenidate (51 [40%] of 129 patients). Three serious adverse events occurred during the study (pulmonary embolism and myocarditis while taking amantadine, and a multiple sclerosis exacerbation requiring hospital admission while taking modafinil).

Interpretation: Amantadine, modafinil, and methylphenidate were not superior to placebo in improving multiple sclerosis fatigue and caused more frequent adverse events. The results of this study do not support an indiscriminate use of amantadine, modafinil, or methylphenidate for the treatment of fatigue in multiple sclerosis.

Funding: Patient-Centered Outcomes Research Institute.
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http://dx.doi.org/10.1016/S1474-4422(20)30354-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772747PMC
January 2021

Corneal epithelial dendritic cells in patients with multiple sclerosis: An in vivo confocal microscopy study.

J Clin Neurosci 2020 Nov 10;81:139-143. Epub 2020 Oct 10.

Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Italy; Ospedale Policlinico San Martino IRCCS, Genoa, Italy. Electronic address:

Purpose: To evaluate density and morphology of corneal epithelial dendritic cells (DCs) in patients with multiple sclerosis (MS) using in vivo confocal microscopy (IVCM).

Methods: This was a single-center cross-sectional comparative study. All MS patients were clinically scored using the Expanded Disability Status Scale (EDSS) score. Patients underwent ophthalmological examination and then cornea was analyzed by IVCM Heidelberg Retina Tomograph (HRT 3) in combination with Rostock Cornea Module and CCD camera. Five sectors (central, nasal, temporal, inferior, superior and central area) were analyzed in both patient eyes, then for each sector one image was selected and analyzed by using the manual cell counting system offered with the software and ImageJ program. DCs density (cell/mm) and DCs size (µm) were considered for the analyses. Difference between the two groups and correlation between DCs, MS type, EDSS score, optic neuritis and ongoing therapy were analyzed.

Results: We enrolled 46 consecutive patients: 23 with MS (age 47.87 ± 7.22 years (mean ± standard deviation) and 21 healthy subjects (age 46.0 ± 12.6 years) from July 2017 to July 2018. MS patients showed a lower DCs density when compared with healthy subjects (p < 0.05). Moreover, we found a direct correlation (r:0.48, p < 0.05) between DCs density and ongoing disease-modifying therapy.

Conclusion: IVCM was able to show a difference in corneal DCs density between MS patients and healthy subjects, providing an insight to the underlying changes of the clinical manifestations of MS. Further studies are needed to provide evidence of possible clinical implications.
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http://dx.doi.org/10.1016/j.jocn.2020.09.041DOI Listing
November 2020

Contrast-induced encephalopathy mimicking total anterior circulation stroke: a case report and review of the literature.

Neurol Sci 2021 Mar 22;42(3):1145-1150. Epub 2020 Oct 22.

Neurological Department, "A. Manzoni" Hospital, ASST Lecco, Via dell'Eremo 9/11, 23900, Lecco, Italy.

Introduction: Contrast-induced encephalopathy is a rare and usually reversible entity due to the administration of iodinated contrast. Clinical manifestations include cortical blindness, encephalopathy, seizures and focal neurological deficits.

Methods: We report the case of a 56-year-old woman who developed global aphasia and right hemiplegia after a cerebral angiography performed for a subarachnoid haemorrhage. A prompt brain MRI resulted negative, while CT scan revealed left cerebral oedema with the cerebral sulci effacement. Complete recovery was observed in 10 days.

Discussion: Diagnosis of contrast-induced encephalopathy requires a temporal correlation between neurological dysfunction and administration of iodinated contrast. Usually, the symptomatology is transient with a full recovery within 48-72 h. The most common symptom is cortical blindness, while other symptoms have been rarely reported. Only 20 cases previously reported global aphasia and/or hemiplegia or mimed anterior circulation strokes. Prompt brain neuroimaging is essential in order to exclude an alternative diagnosis that requires a distinct therapeutic approach.
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http://dx.doi.org/10.1007/s10072-020-04844-1DOI Listing
March 2021

Retinal INL Thickness in Multiple Sclerosis: A Mere Marker of Neurodegeneration?

Ann Neurol 2021 01 11;89(1):192-193. Epub 2020 Nov 11.

Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA.

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http://dx.doi.org/10.1002/ana.25933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990472PMC
January 2021

Genetics of dementia: insights from Latin America.

Dement Neuropsychol 2020 Jul-Sep;14(3):223-236

Neurosciences Group of Antioquia, School of Medicine, Universidad de Antioquia - Medellín, Colombia.

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are neurodegenerative disorders that result in a significant burden to both patients and caregivers. By 2050, the number of people with dementia in Latin America will increase 4-fold. A deep understanding of the relevant genetic factors of AD and FTD is fundamental to tackle this reality through prevention. A review of different genetic variants that cause AD or FTD in Latin America was conducted. We searched Medline and PubMed databases using the keywords "Alzheimer's disease," "frontotemporal dementia," "mutation," "America," and "Latin America," besides specific Latin American countries. Forty-five items were chosen and analyzed. mutations are the commonest cause of genetic early-onset Alzheimer's disease (EOAD), followed by and mutations. Genetic FTD can be mainly explained by and mutations, as well as repeat expansion. ε4 can modify the prevalence and incidence of late-onset Alzheimer's disease (LOAD), in addition to the cognitive performance in affected carriers.
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http://dx.doi.org/10.1590/1980-57642020dn14-030004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500810PMC
September 2020

Mild COVID-19 infection in a group of teriflunomide-treated patients with multiple sclerosis.

J Neurol 2021 Jun 31;268(6):2029-2030. Epub 2020 Aug 31.

Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.

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http://dx.doi.org/10.1007/s00415-020-10196-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457441PMC
June 2021

Assessing the susceptibility to acute respiratory illness COVID-19-related in a cohort of multiple sclerosis patients.

Mult Scler Relat Disord 2020 Nov 19;46:102453. Epub 2020 Aug 19.

UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.

Introduction: Italy has been the first European country severely affected by the COVID-19 pandemic.

Objective: To analyze the incidence of the clinical presentations suggestive for COVID-19 infection among patients with Multiple Sclerosis in the province of Lecco, in the North Italy, the closest province capital to Bergamo. To describe the association of demographics, clinical characteristics, and use of DMTs categories with the risk of contracting the disease.

Methods: We telephonically interviewed all the 275 MS patients followed in the MS center. The collected data included recent contact with a patient with COVID-19 diagnosis or a subject with respiratory symptoms and the developing of COVID-19 symptoms or a confirmed diagnosis.

Results: 15 out of 275 patients reported symptoms suggestive for COVID-19 infection, only one of them with PCR-confirmed diagnosis. No one of them presented severe symptoms or needed hospitalization. Using a multivariable logistic regression model, the only factor associated with being in the COVID-suspect group was the report of a recent contact with a patient with a COVID-19 diagnosis.

Conclusions: The prevalence of COVID-19 within MS patients seems to resemble the prevalence in general population. The lack of associations with other factors assessed, including DMTs, may reflect a lack of statistical power. Larger population studies are needed to explore the correlation between different disease-modifying therapies and COVID-19 course.
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http://dx.doi.org/10.1016/j.msard.2020.102453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434623PMC
November 2020

Imaging correlates of visual function in multiple sclerosis.

PLoS One 2020 3;15(8):e0235615. Epub 2020 Aug 3.

Division of Neuroimmunology and Glial Biology UCSF, Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, United States of America.

No single neuroimaging technique or sequence is capable of reflecting the functional deficits manifest in MS. Given the interest in imaging biomarkers for short- to medium-term studies, we aimed to assess which imaging metrics might best represent functional impairment for monitoring in clinical trials. Given the complexity of functional impairment in MS, however, it is useful to isolate a particular functionally relevant pathway to understand the relationship between imaging and neurological function. We therefore analyzed existing data, combining multiparametric MRI and OCT to describe MS associated visual impairment. We assessed baseline data from fifty MS patients enrolled in ReBUILD, a prospective trial assessing the effect of a remyelinating drug (clemastine). Subjects underwent 3T MRI imaging, including Neurite Orientation Dispersion and Density Imaging (NODDI), myelin content quantification, and retinal imaging, using OCT. Visual function was assessed, using low-contrast letter acuity. MRI and OCT data were studied to model visual function in MS, using a partial, least-squares, regression analysis. Measures of neurodegeneration along the entire visual pathway, described most of the observed variance in visual disability, measured by low contrast letter acuity. In those patients with an identified history of ON, however, putative myelin measures also showed correlation with visual performance. In the absence of clinically identifiable inflammatory episodes, residual disability correlates with neurodegeneration, whereas after an identifiable exacerbation, putative measures of myelin content are additionally informative.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235615PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398529PMC
September 2020

MRI Measurement of Upper Cervical Spinal Cord Cross-Sectional Area in Children.

J Neuroimaging 2020 09 8;30(5):598-602. Epub 2020 Jul 8.

UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, CA.

Background And Purpose: Neurological and neurodegenerative diseases can affect the spinal cord (SC) of pediatric patients. Magnetic resonance imaging (MRI) allows for in vivo quantification of SC atrophy via cross-sectional area (CSA). The study of CSA values in the general population is important to disentangle disease-related changes from intersubject variability. This study aimed at providing normative values for cervical CSA in children, extending our previous work performed with adults.

Methods: Seventy-eight children (age 7-17 years) were selected from a Developmental Dyslexia study. All subjects underwent a 3T brain MRI session and any incidental findings were reported on the scans. A sagittal 1 mm 3-dimensional T -weighted brain acquisition extended to the upper cervical cord was used to measure CSA at C2-C3, as well as spinal canal area and skull volume (V-scale). These three metrics were linearly fitted as a function of age to extract trends and percentage annual changes. Sex differences of CSA were assessed using least squares regression analyses, adjusting for age. We tested normalization strategies proven to be effective in reducing the intersubject variability of adults' CSA.

Results: CSA changed as a function of age at a faster rate when compared with skull volume (CSA: 1.82% increase, V-scale: .60% reduction). Sex had a statistically significant effect on CSA. Normalization methods based on canal area and skull volume reduced the CSA intersubject variability up to 16.84%.

Conclusions: We present CSA normative values in a large cohort of children, reporting on sources of intersubject variability and how to reduce them applying normalization methods previously developed.
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http://dx.doi.org/10.1111/jon.12758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530010PMC
September 2020

COVID-19 in dimethyl fumarate-treated patients with multiple sclerosis.

J Neurol 2021 Jun 25;268(6):2023-2025. Epub 2020 Jun 25.

Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, USA.

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http://dx.doi.org/10.1007/s00415-020-10015-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314911PMC
June 2021

Fixational microsaccades: A quantitative and objective measure of disability in multiple sclerosis.

Mult Scler 2020 03 7;26(3):343-353. Epub 2020 Feb 7.

Department of Neurology, University of California, San Francisco, San Francisco, CA, USA/Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, USA.

Background: Objective tools for prognosis and disease progression monitoring in multiple sclerosis (MS) are lacking. The visuomotor system could be used to track motor dysfunction at the micron scale through the monitoring of fixational microsaccades.

Aims: The aim of this study was to evaluate whether microsaccades are correlated with standard MS disability metrics and to assess whether these methods play a predictive role in MS disability.

Method: We used a custom-built retinal eye tracker, the tracking scanning laser ophthalmoscope (TSLO), to record fixation in 111 participants with MS and 100 unaffected controls.

Results: In MS participants, a greater number of microsaccades showed significant association with higher Expanded Disability Status Scale score (EDSS,  < 0.001), nine-hole peg test (non-dominant:  = 0.006), Symbol Digit Modalities Test (SMDT,  = 0.014), and Functional Systems Scores (FSS) including brainstem ( = 0.005), cerebellar ( = 0.011), and pyramidal ( = 0.009). Both brainstem FSS and patient-reported fatigue showed significant associations with microsaccade number, amplitude, and peak acceleration. Participants with MS showed a statistically different average number ( = 0.020), peak vertical acceleration ( = 0.003), and vertical amplitude ( < 0.001) versus controls. Logistic regression models for MS disability were created using TSLO microsaccade metrics and paraclinical tests with ⩾80% accuracy.

Conclusion: Microsaccades provide objective measurements of MS disability level and disease worsening.
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http://dx.doi.org/10.1177/1352458519894712DOI Listing
March 2020

Monitoring retinal changes with optical coherence tomography predicts neuronal loss in experimental autoimmune encephalomyelitis.

J Neuroinflammation 2019 Nov 4;16(1):203. Epub 2019 Nov 4.

Division of Neuroimmunology and Glial Biology, Department of Neurology, University of California, San Francisco, San Francisco, USA.

Background: Retinal optical coherence tomography (OCT) is a clinical and research tool in multiple sclerosis, where it has shown significant retinal nerve fiber (RNFL) and ganglion cell (RGC) layer thinning, while postmortem studies have reported RGC loss. Although retinal pathology in experimental autoimmune encephalomyelitis (EAE) has been described, comparative OCT studies among EAE models are scarce. Furthermore, the best practices for the implementation of OCT in the EAE lab, especially with afoveate animals like rodents, remain undefined. We aimed to describe the dynamics of retinal injury in different mouse EAE models and outline the optimal experimental conditions, scan protocols, and analysis methods, comparing these to histology to confirm the pathological underpinnings.

Methods: Using spectral-domain OCT, we analyzed the test-retest and the inter-rater reliability of volume, peripapillary, and combined horizontal and vertical line scans. We then monitored the thickness of the retinal layers in different EAE models: in wild-type (WT) C57Bl/6J mice immunized with myelin oligodendrocyte glycoprotein peptide (MOG) or with bovine myelin basic protein (MBP), in TCR mice immunized with MOG, and in SJL/J mice immunized with myelin proteolipid lipoprotein (PLP). Strain-matched control mice were sham-immunized. RGC density was counted on retinal flatmounts at the end of each experiment.

Results: Volume scans centered on the optic disc showed the best reliability. Retinal changes during EAE were localized in the inner retinal layers (IRLs, the combination of the RNFL and the ganglion cell plus the inner plexiform layers). In WT, MOG EAE, progressive thinning of IRL started rapidly after EAE onset, with 1/3 of total loss occurring during the initial 2 months. IRL thinning was associated with the degree of RGC loss and the severity of EAE. Sham-immunized SJL/J mice showed progressive IRL atrophy, which was accentuated in PLP-immunized mice. MOG-immunized TCR mice showed severe EAE and retinal thinning. MBP immunization led to very mild disease without significant retinopathy.

Conclusions: Retinal neuroaxonal damage develops quickly during EAE. Changes in retinal thickness mirror neuronal loss and clinical severity. Monitoring of the IRL thickness after immunization against MOG in C57Bl/6J mice seems the most convenient model to study retinal neurodegeneration in EAE.
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http://dx.doi.org/10.1186/s12974-019-1583-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827223PMC
November 2019

Relationship between retinal inner nuclear layer, age, and disease activity in progressive MS.

Neurol Neuroimmunol Neuroinflamm 2019 09 12;6(5). Epub 2019 Aug 12.

From the Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI) (M.C., C.C., G. Boffa, G. Bommarito, E.S., G.N., C.L., A.U., M.I.), University of Genoa, Italy; Department of Neurology (C.C.), Multiple Sclerosis Center, University of California, San Francisco; Departments of Neurology, Radiology and Neuroscience (M.P., M.I.), Icahn School of Medicine at Mount Sinai, New York; and Ospedale Policlinico San Martino-IRCCS (E.C., A.U., M.I.), Genoa, Italy.

Objective: To investigate whether inner nuclear layer (INL) thickness as assessed with optical coherence tomography differs between patients with progressive MS (P-MS) according to age and disease activity.

Methods: In this retrospective longitudinal analysis, differences in terms of peripapillary retinal nerve fiber layer (pRNFL), ganglion cell layer + inner plexiform layer (GCIPL), INL and T1/T2 lesion volumes (T1LV/T2LV) were assessed between 84 patients with P-MS and 36 sex- and age-matched healthy controls (HCs) and between patients stratified according to age (cut-off: 51 years) and evidence of clinical/MRI activity in the previous 12 months RESULTS: pRNFL and GCIPL thickness were significantly lower in patients with P-MS than in HCs ( = 0.003 and < 0.0001, respectively). INL was significantly thicker in patients aged < 51 years compared to the older ones and HCs (38.2 vs 36.5 and 36.7 μm; = 0.038 and = 0.04, respectively) and in those who presented MRI activity (new T2/gadolinium-enhancing lesions) in the previous 12 months compared to the ones who did not and HCs (39.5 vs 36.4 and 36.7 μm; = 0.003 and = 0.008, respectively). Recent MRI activity was significantly predicted by greater INL thickness (Nagelkerke R 0.36, = 0.001).

Conclusions: INL thickness was higher in younger patients with P-MS with recent MRI activity, a criterion used in previous studies to identify a specific subset of patients with P-MS who best responded to disease-modifying treatment. If this finding is confirmed, we suggest that INL thickness might be a useful tool in stratification of patients with P-MS for current and experimental treatment choice.
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http://dx.doi.org/10.1212/NXI.0000000000000596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705649PMC
September 2019

pRNFL as a marker of disability worsening in the medium/long term in patients with MS.

Neurol Neuroimmunol Neuroinflamm 2019 03 21;6(2):e533. Epub 2018 Dec 21.

Department of Neurology (C.C., M.D., V.D., D.B., S.L.H., B.A.C.C., J.M.G., A.J.G.), UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA; and Department of Neurology (B.N.), Johns Hopkins University School of Medicine, Baltimore, MD.

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http://dx.doi.org/10.1212/NXI.0000000000000533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340330PMC
March 2019

Prion Seeds Distribute throughout the Eyes of Sporadic Creutzfeldt-Jakob Disease Patients.

mBio 2018 11 20;9(6). Epub 2018 Nov 20.

Department of Pathology, University of California, San Diego, La Jolla, California, USA

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common prion disease in humans and has been iatrogenically transmitted through corneal graft transplantation. Approximately 40% of sCJD patients develop visual or oculomotor symptoms and may seek ophthalmological consultation. Here we used the highly sensitive real-time quaking-induced conversion (RT-QuIC) assay to measure postmortem prion seeding activities in cornea, lens, ocular fluid, retina, choroid, sclera, optic nerve, and extraocular muscle in the largest series of sCJD patient eyes studied by any assay to date. We detected prion seeding activity in 100% of sCJD eyes, representing three common sCJD subtypes, with levels varying by up to 4 log-fold among individuals. The retina consistently showed the highest seed levels, which in some cases were only slightly lower than brain. Within the retina, prion deposits were detected by immunohistochemistry (IHC) in the retinal outer plexiform layer in most sCJD cases, and in some eyes the inner plexiform layer, consistent with synaptic prion deposition. Prions were not detected by IHC in any other eye region. With RT-QuIC, prion seed levels generally declined in eye tissues with increased distance from the brain, and yet all corneas had prion seeds detectable. Prion seeds were also present in the optic nerve, extraocular muscle, choroid, lens, vitreous, and sclera. Collectively, these results reveal that sCJD patients accumulate prion seeds throughout the eye, indicating the potential diagnostic utility as well as a possible biohazard. Cases of iatrogenic prion disease have been reported from corneal transplants, yet the distribution and levels of prions throughout the eye remain unknown. This study probes the occurrence, level, and distribution of prions in the eyes of patients with sporadic Creutzfeldt-Jakob disease (sCJD). We tested the largest series of prion-infected eyes reported to date using an ultrasensitive technique to establish the prion seed levels in eight regions of the eye. All 11 cases had detectable prion seeds in the eye, and in some cases, the seed levels in the retina approached those in brain. In most cases, prion deposits could also be seen by immunohistochemical staining of retinal tissue; other ocular tissues were negative. Our results have implications for estimating the risk for iatrogenic transmission of sCJD as well as for the development of antemortem diagnostic tests for prion diseases.
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http://dx.doi.org/10.1128/mBio.02095-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247090PMC
November 2018

Acquired Hepatocerebral Degeneration in the Absence of Portosystemic Shunting.

J Clin Neurol 2019 Jan 26;15(1):128-129. Epub 2018 Oct 26.

Department of Neurology, San Paolo Hospital, Savona, Italy.

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http://dx.doi.org/10.3988/jcn.2019.15.1.128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325363PMC
January 2019

Oligodendrocyte-encoded Kir4.1 function is required for axonal integrity.

Elife 2018 09 11;7. Epub 2018 Sep 11.

Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, United States.

Glial support is critical for normal axon function and can become dysregulated in white matter (WM) disease. In humans, loss-of-function mutations of which encodes the inward-rectifying potassium channel KIR4.1, causes seizures and progressive neurological decline. We investigated Kir4.1 functions in oligodendrocytes (OLs) during development, adulthood and after WM injury. We observed that Kir4.1 channels localized to perinodal areas and the inner myelin tongue, suggesting roles in juxta-axonal K removal. Conditional knockout (cKO) of OL- resulted in late onset mitochondrial damage and axonal degeneration. This was accompanied by neuronal loss and neuro-axonal dysfunction in adult OL- cKO mice as shown by delayed visual evoked potentials, inner retinal thinning and progressive motor deficits. Axon pathologies in OL- cKO were exacerbated after WM injury in the spinal cord. Our findings point towards a critical role of OL-Kir4.1 for long-term maintenance of axonal function and integrity during adulthood and after WM injury.
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http://dx.doi.org/10.7554/eLife.36428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167053PMC
September 2018

Determining the Etiology of Internuclear Ophthalmoplegia in a Patient with a Cardiac Pacemaker and Complex Neurological Presentation.

J Clin Neurol 2018 Oct 6;14(4):574-576. Epub 2018 Sep 6.

Department of Neurology, Massachusetts General Hospital, Harvard University, Boston, MA, USA.

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http://dx.doi.org/10.3988/jcn.2018.14.4.574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172500PMC
October 2018

Osteopathic Manipulative Therapy and Multiple Sclerosis: A Proof-of-Concept Study.

J Am Osteopath Assoc 2018 Aug;118(8):531-536

Context: Research on the effect of osteopathic manipulative therapy (OMTh; manipulative care provided by foreign-trained osteopaths) on chronic symptoms of multiple sclerosis (MS) is lacking.

Objective: To evaluate the effect of OMTh on chronic symptoms of MS.

Methods: Patients with MS who were evaluated at the neurology clinic at Genoa University in Italy were recruited for this study. Participants received 5 forty-minute MS health education sessions (control group) or 5 OMTh sessions (OMTh group). All participants completed a questionnaire that assessed their level of clinical disability, fatigue, depression, anxiety, and quality of life before the first session, 1 week after the final session, and 6 months after the final session. The Extended Disability Status Scale, a modified Fatigue Impact Scale, the Beck Depression Inventory-II, the Beck Anxiety Inventory, and the 12-item Short Form Health Survey were used to assess clinical disability, fatigue, depression, anxiety, and quality of life, respectively.

Results: Twenty-two participants were included in the study (10 in the control group and 12 in the OMTh group). In the OMTh group, statistically significant improvements in fatigue and depression were found 1 week after the final session (P=.002 and P<.001, respectively). An increase in quality of life was also found in the OMTh group 1 week after the final session (P=.36).

Conclusion: Results demonstrate that OMTh should be considered in the treatment of patients with chronic symptoms of MS.
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http://dx.doi.org/10.7556/jaoa.2018.121DOI Listing
August 2018

Evaluation of the association between sexual dysfunction and demyelinating plaque location and number in female multiple sclerosis patients.

Neurol Res 2018 Aug 17;40(8):683-688. Epub 2018 Apr 17.

a Department of Neurology , Trakya University Medical Faculty , Edirne , Turkey.

Purpose To investigate the frequency of sexual dysfunction (SD) in female multiple sclerosis (MS) patients and to explore its association with the location and number of demyelinating lesions. Material and Methods We evaluated 42 female patients and 41 healthy subjects. All patients underwent neurological examination and 1.5 T brain and full spinal MRI. All subjects completed the female sexual function index (FSFI), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and Short-Form 36 Quality of Life Scale (SF-36). All participants were also evaluated for serum thyroid stimulating hormone (TSH), T4, estradiol, and total testosterone. Results No statistically significant differences between the MS and control groups were found for age, body mass index (BMI), serum TSH, T4, E2, and total testosterone level. MS patients had a statistically significantly lower FSFI and SF-36 scores and higher BDI and BAI scores compared with healthy subjects. The location and number of demyelinating lesions were not associated with SD. Conclusion In our cohort, this difference in SD appears unrelated to the location and number of demyelinating lesions. These findings highlight the importance of the assessment and treatment of psychiatric comorbidities, such as depression and anxiety, in MS patients reporting SD.
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http://dx.doi.org/10.1080/01616412.2018.1462752DOI Listing
August 2018

MRI Findings in Varicella Zoster Trigeminal Neuritis Without Rash.

Headache 2018 05 5;58(5):764-765. Epub 2018 Feb 5.

Department of Neurology, S. Paolo Hospital, Savona, Italy.

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http://dx.doi.org/10.1111/head.13264DOI Listing
May 2018

Motor Imagery as a Function of Disease Severity in Multiple Sclerosis: An fMRI Study.

Front Hum Neurosci 2017 11;11:628. Epub 2018 Jan 11.

Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Motor imagery (MI) is defined as mental execution without any actual movement. While healthy adults usually show temporal equivalence, i.e., isochrony, between the mental simulation of an action and its actual performance, neurological disorders are associated with anisochrony. Unlike in patients with stroke and Parkinson disease, only a few studies have investigated differences of MI ability in multiple sclerosis (MS). However, the relationship among disease severity, anisochrony and brain activation patterns during MI has not been investigated yet. Here, we propose to investigate MI in MS patients using fMRI during a behavioral task executed with dominant/non-dominant hand and to evaluate whether anisochrony is associated with disease severity. Thirty-seven right-handed MS patients, 17 with clinically isolated syndrome (CIS) suggestive of MS and 20 with relapsing-remitting MS (RR-MS) and 20 right-handed healthy controls (HC) underwent fMRI during a motor task consisting in the actual or imaged movement of squeezing a foam ball with the dominant and non-dominant hand. The same tasks were performed outside the MRI room to record the number of actual and imagined ball squeezes, and calculate an Index of performance (IP) based on the ratio between actual and imagined movements. IP showed that a progressive loss of ability in simulating actions (i.e., anisochrony) more pronounced for non-dominant hand, was found as function of the disease course. Moreover, anisochrony was associated with activation of occipito-parieto-frontal areas that were more extensive at the early stages of the disease, probably in order to counteract the changes due to MS. However, the neural engagement of compensatory brain areas becomes more difficult with more challenging tasks, i.e., dominant vs. non-dominant hand, with a consequent deficit in behavioral performance. These results show a strict association between MI performance and disease severity, suggesting that, at early stages of the disease, anisochrony in MI could be considered as surrogate behavioral marker of MS severity.
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http://dx.doi.org/10.3389/fnhum.2017.00628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768615PMC
January 2018

Advances in Imaging Multiple Sclerosis.

Semin Neurol 2017 10 5;37(5):538-545. Epub 2017 Dec 5.

Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California.

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http://dx.doi.org/10.1055/s-0037-1607278DOI Listing
October 2017

Occipital Headache in Chronic Lymphocytic Inflammation With Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS).

Headache 2018 03 28;58(3):458-459. Epub 2017 Nov 28.

Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.

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http://dx.doi.org/10.1111/head.13232DOI Listing
March 2018

Extensive Involvement of Multiple Cranial and Spinal Nerves in Lymphomatous Meningitis.

Can J Neurol Sci 2017 09 9;44(5):599-600. Epub 2017 May 9.

2Department of Radiology,University of California San Francisco,San Francisco,California.

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http://dx.doi.org/10.1017/cjn.2017.50DOI Listing
September 2017

Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis.

Sci Transl Med 2017 04;9(385)

Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.

Heterozygous mutations in the gene lead to progranulin (PGRN) haploinsufficiency and cause frontotemporal dementia (FTD), a neurodegenerative syndrome of older adults. Homozygous mutations, on the other hand, lead to complete PGRN loss and cause neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease usually seen in children. Given that the predominant clinical and pathological features of FTD and NCL are distinct, it is controversial whether the disease mechanisms associated with complete and partial PGRN loss are similar or distinct. We show that PGRN haploinsufficiency leads to NCL-like features in humans, some occurring before dementia onset. Noninvasive retinal imaging revealed preclinical retinal lipofuscinosis in heterozygous mutation carriers. Increased lipofuscinosis and intracellular NCL-like storage material also occurred in postmortem cortex of heterozygous mutation carriers. Lymphoblasts from heterozygous mutation carriers accumulated prominent NCL-like storage material, which could be rescued by normalizing PGRN expression. Fibroblasts from heterozygous mutation carriers showed impaired lysosomal protease activity. Our findings indicate that progranulin haploinsufficiency caused accumulation of NCL-like storage material and early retinal abnormalities in humans and implicate lysosomal dysfunction as a central disease process in -associated FTD and -associated NCL.
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http://dx.doi.org/10.1126/scitranslmed.aah5642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526610PMC
April 2017

Homonymous hemianopia as the first sign of posterior cortical atrophy.

J Neurol Sci 2017 Feb 14;373:38-40. Epub 2016 Dec 14.

Department of Neurology, S. Paolo Hospital, Savona, Italy.

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http://dx.doi.org/10.1016/j.jns.2016.12.016DOI Listing
February 2017
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