Importance: A robust cerebrospinal fluid (CSF) cell cryopreservation protocol using high resoluti... more Importance: A robust cerebrospinal fluid (CSF) cell cryopreservation protocol using high resolution single-cell (sc) transcriptomic data would enable the deployment of this important modality in multi-center translational research studies and clinical trials in which many sites do not have the expertise or resources to produce data from fresh samples. It would also serve to reduce technical variability in larger projects. Objective: To test a reliable cryopreservation protocol adapted for CSF cells, facilitating the characterization of these rare, fragile cells in moderate to large scale studies. Design: Diagnostic lumbar punctures were performed on twenty-one patients at two independent sites. Excess CSF was collected and cells were isolated. Each cell sample was split into two fractions for single cell analysis using one of two possible chemistries: 3′ sc-RNA-Sequencing or 5 ′ sc-RNA-Sequencing. One cell fraction was processed fresh while the second sample was cryopreserved and pr...
A 71-year-old woman previously on rituximab treatment for rheumatoid arthritis presented with 2 y... more A 71-year-old woman previously on rituximab treatment for rheumatoid arthritis presented with 2 years of progressive neurologic symptoms. She was found to have persistent hypogammaglobulinemia and B cell depletion despite rituximab discontinuation a year prior. MRI revealed diffuse meningeal enhancement along the entire neuroaxis. LP showed a CSF lymphocytic pleocytosis, elevated protein, and presence of enterovirus by PCR. The patient was hospitalized several times for progressive clinical and radiologic decline, though she had transient improvements following treatment with immunoglobulin therapy. Her CSF remained positive for enterovirus PCR for at least 12 months. Though two brain biopsies were non-diagnostic, pan- Enterovirus was ultimately identified using a high-throughput next-generation sequencing technique. She was treated with compassionate-use pocapavir with clinical stabilization at 4-month follow-up; however, she expired 8 months later from a bacterial pneumonia.
OBJECTIVE: To compare brain temperature between patients with relapsing-remitting (RR) and progre... more OBJECTIVE: To compare brain temperature between patients with relapsing-remitting (RR) and progressive courses of multiple sclerosis (MS). BACKGROUND: We recently reported elevated body temperature in RRMS relative to healthy individuals and progressive MS patients in the absence of exogenous heat exposure (Sumowski & Leavitt, 2014), an observation never before reported despite the long-standing literature describing negative consequences of experimental and environmental heat exposure in MS patients (i.e., Uhthoff’s phenomenon). Elevated body temperature may result from clinically-silent brain inflammation in RRMS. If so, brain temperature should also be elevated in RRMS patients. Here, we examined brain temperature in RRMS patients versus progressive MS. METHODS: We used MR spectroscopy to derive brain temperature in 14 patients (9 RRMS, 3 SPMS, 2 PPMS). MRS permits non-invasive measurement of brain temperature because hydrogen bonding is temperature-dependent; measuring the shift...
Objective: To conduct a randomized, double-blind crossover design pilot trial of aspirin as a pre... more Objective: To conduct a randomized, double-blind crossover design pilot trial of aspirin as a pretreatment to improve exercise performance in patients with multiple sclerosis (MS). Background: Exercise is only beneficial if people do it. Many MS patients are deterred from exercising by overheating and exhaustion (“Uhthoff’s phenomenon”). We tested aspirin, an antipyretic, to improve exercise performance and reduce exercise-induced body temperature increase in persons with MS. Design/Methods: Twelve MS patients participated. At enrollment, 8 of 12 participants reported heat-sensitivity. All participants completed two exercise sessions separated by one week. At each session, participants were administered a standard dose (650 mg) of aspirin or placebo. After one hour, participants performed a progressive ramped maximal exercise test (lower body cycle ergometer). Test was terminated when volitional exhaustion was reached. Paired samples t-tests were conducted to evaluate differences in...
Objective: To determine the effect of Natalizumab on the degree of inflammation after 3 and 6 mon... more Objective: To determine the effect of Natalizumab on the degree of inflammation after 3 and 6 months of treatment, using PK11195-PET. Background: The pathogenesis of MS is characterized by the influx of leukocytes from the periphery into the CNS, inducing a pro-inflammatory environment. This leads to stimulation of the innate immune system and causes subsequent microglia/macrophage activation. Natalizumab is a humanized antibody against the cell adhesion molecule alpha 4-integrin, preventing leukocytes from crossing endothelial borders. However, the effect of Natalizumab on the innate immune system is unknown. PK11195-PET is used to detect microglia/macrophage activation by binding translocator protein (TSPO), a protein found on the outer mitochondrial membrane of microglia/macrophages. Methods: For this longitudinal study 18 patients, starting Natalizumab, were included. PK11195-PET scans were acquired at baseline, 3 and 6 months post Natalizumab treatment. PK uptake was quantified...
The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a global... more The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a global effort to rapidly develop and deploy effective and safe coronavirus disease 2019 (COVID-19) vaccinations. Vaccination has been one of the most effective medical interventions in human history, although potential safety risks of novel vaccines must be monitored, identified, and quantified. Adverse events must be carefully assessed to define whether they are causally associated with vaccination or coincidence. Neurologic adverse events following immunizations are overall rare but with significant morbidity and mortality when they occur. Here, we review neurologic conditions seen in the context of prior vaccinations and the current data to date on select COVID-19 vaccines including mRNA vaccines and the adenovirus-vector COVID-19 vaccines, ChAdOx1 nCOV-19 (AstraZeneca) and Ad26.COV2.S Johnson & Johnson (Janssen/J&J).
Multiple Sclerosis Journal - Experimental, Translational and Clinical, 2020
We report a fatal case of COVID-19 in a 51-year-old African American woman with multiple sclerosi... more We report a fatal case of COVID-19 in a 51-year-old African American woman with multiple sclerosis on natalizumab. She had multiple risk factors for severe COVID-19 disease including race, obesity, hypertension, and elevated inflammatory markers, but the contribution of natalizumab to her poor outcome remains unknown. We consider whether altered dynamics of peripheral immune cells in the context of natalizumab treatment could worsen the cytokine storm syndrome associated with severe COVID-19. We discuss extended interval dosing as a risk-reduction strategy for multiple sclerosis patients on natalizumab, and the use of interleukin-6 inhibitors in such patients who contract COVID-19.
ObjectiveTo test the hypothesis that higher-challenge gait and balance tasks are more sensitive t... more ObjectiveTo test the hypothesis that higher-challenge gait and balance tasks are more sensitive than traditional metrics to subtle patient-reported gait dysfunction and future fall risk in early multiple sclerosis (MS).MethodsPersons with early MS (n = 185; ≤5 years diagnosed) reported gait function (MS Walking Scale) and underwent traditional disability metrics (Expanded Disability Status Scale [EDSS], Timed 25 Foot Walk). Patients and healthy controls (n = 50) completed clinically feasible challenge tasks of gait endurance (2-Minute Walk Test), standing balance (NIH Toolbox), and dynamic balance (balance boards; tandem walk on 2 ten-foot boards of different widths, 4.5 and 1.5 in). MRI assessed global and regional brain volumes, total T2 lesion volume (T2LV), infratentorial T2LVs and counts, and cervical cord lesion counts. Falls, near falls, and fall-related injuries were assessed after 1 year. We examined links between all tasks and patient-reported gait, MRI markers, and fall d...
Background: Persons with multiple sclerosis (MS) commonly report word-finding difficulty clinical... more Background: Persons with multiple sclerosis (MS) commonly report word-finding difficulty clinically, yet this language deficit remains underexplored. Objective: To investigate the prevalence and nature of word-finding difficulty in persons with early MS on three levels: patient report, cognitive substrates, and neuroimaging. Methods: Two samples of early MS patients ( n = 185 and n = 55; ⩽5 years diagnosed) and healthy controls ( n = 50) reported frequency/severity of cognitive deficits and underwent objective assessment with tasks of rapid automatized naming (RAN), measuring lexical access speed, memory, word generation, and cognitive efficiency. High-resolution brain magnetic resonance imaging (MRI) derived measurements of regional cortical thickness, global and deep gray matter volume, and T2 lesion volume. Relationships among patient-reported word-finding difficulty, cognitive performance, and neural correlates were examined. Results: Word-finding difficulty was the most common ...
Learning Objectives Upon completion of this activity, the participant will be able to: & Iden... more Learning Objectives Upon completion of this activity, the participant will be able to: & Identify normal anatomic landmarks on brain and spine MRIs & Formulate a differential diagnosis for lesions on brain and spine MRIs & Understand the limitations of current imaging techniques Address correspondence to Dr Riley Bove, University of California, San Francisco Sandler Neurosciences Center, 675 Nelson Rising Ln, San Francisco, CA 94158, Riley.Bove@ucsf.edu.
OBJECTIVE: 1) to measure cervical spinal cord (SC) atrophy in patients with primary-progressive m... more OBJECTIVE: 1) to measure cervical spinal cord (SC) atrophy in patients with primary-progressive multiple sclerosis (PP-MS); 2) to investigate the relationship between cervical SC atrophy and measures of brain volume, gray matter (GM) cortical lesion (CL) volume and count; 3) to determine the clinical impact of cervical SC atrophy. BACKGROUND: SC atrophy is a typical feature of PP-MS but the relationship with regional and global brain pathology especially in the GM is not well understood DESIGN/METHODS: As part of an ongoing study, s ixteen PP-MS patients (7M; mean age: 53.8±8.7; median EDSS: 4.0, range:1.5-6.0) and 16 age and gender matched CTRLs (7M; mean age: 53.0±9.2) underwent MRI at 3T. The MRI protocol included a) brain dual-echo; b) 3D T1-weighted; c) double inversion recovery (DIR); d) spine T2-weighted TSE; e) 3D T1-weighted.Normalized whole brain (NBV), white matter (WM) and GM volumes were measured as well as GM CL volume and count. Normalized cervical cord cross sectional area (CSAn) and spine volume (CSVn) was measured from C1 to C7 (total_CSAn and CSVn) and at C2 level (C2_CSVn). Between-group comparisons were assessed using a 2-sample t-test and the associations using Spearman’s rank correlation coefficient. RESULTS: NBV and GM volume, but not WM volume, were significantly lower in patients than in CTRLs (p 0.16±0.02 ml in patients and 0.23±0.01ml and 0.18±0.01ml in CTRLs (p 2 in patients and 74.6±6.4mm 2 in CTRLs (p<0.05). A trend of statistical significance was present between the C2_CSVn and the WM volume (p=0.06) and C2_CSVn and the left 9HPT (p=0.08); CONCLUSIONS: In PP-MS cord atrophy correlates with clinical disability and it is modestly associated with brain WM volume but not with GM brain and lesion load. Study Supported by: partially by Novartis Pharmaceuticals Disclosure: Dr. Teodorescu has nothing to disclose. Dr. Petracca has nothing to disclose. Dr. Farrell has nothing to disclose. Dr. Howard has nothing to disclose. Dr. Riley has received personal compensation for activities with Biogen Idec, EMD Serono, Pfizer Inc., Teva Neuroscience, and Bayer Pharmaceuticals Corp. Dr. Fabian has received personal compensation for activities with Biogen Idec. as a speaker. Dr. Lublin has received personal compensation for activities with Biogen Idec, EMD Serono, Inc., Novartis, Teva Neuroscience, Actelion, Sanofi-Aventis Pharmaceuticals, Inc., Acorda Therapeutis, Questcor, Roche, Genentech, Inc., Celgene, Johnson & Johnson, Revalesio, Coronado Bioscience, Genzyme Corporation, MedImmune, Bristol-Myers Squibb Company, Xenoport, Receptos, Forward Pharma, and Osmotica. Dr. Lublin has received personal compensation in an editorial capacity for Multiple Sclerosis and Related Diseases. Dr. Lublin has received research support from Acorda Therapeutics, Inc., Biogen Idec, Novartis, Teva Neuroscience, Genzyme Corporation, Sanofi-Aventis Pharmaceuticals, Inc., Celgene, National Institutes of Health, and the National Multiple Sclerosis Society. Dr. Inglese has received research support from Novartis Pharmaceuticals.
OBJECTIVE: 1) to characterize brain gray and white matter (GM, WM) injury in patients with primar... more OBJECTIVE: 1) to characterize brain gray and white matter (GM, WM) injury in patients with primary-progressive MS (PP-MS) using diffusional kurtosis imaging (DKI); 2) to investigate the associations between GM and WM DKI/DTI-derived parameters: mean diffusivity (MD), fractional anisotropy (FA), mean kurtosis (MK), axonal water fraction (AWF), tortuosity (ɑ), intraxonal diffusivity (D_axon) and cognitive impairment as measured by MACFIMS neuropsychological (NP) battery BACKGROUND: Although disability in PP-MS is believed to be predominantly due to spinal cord pathology, there is increasing evidence of cognition impairment. However, the underlying mechanisms are still not clear. DESIGN/METHODS: Sixteen PP-MS patients from an undergoing longitudinal study (7M; mean age: 53.8±8.7 yrs; median EDSS: 4.0) and 16 age and gender matched CTRLs (7M; mean age: 53.0±9.2 yrs) were administered the MACFIMS and underwent MRI at 3T. A twice-refocused EPI sequence (30 directions, voxel resolution 2mm3) was used for DKI/DTI. After DTI/DKI maps were derived voxelwise, TBSS was used for the analysis. In addition NBV, WM and GM volumes were measured as well as WM and GM cortical lesion (CL) volume and count. The between-group differences were determined with randomise function of FSL (p<0.05 TFCE-corrected). Associations with NP tests were assessed with Spearman’s correlation coefficient RESULTS: NBV and GM volume, but not WM volume, were significantly lower in patients than in CTRLs (p<0.05). T2-LV and T1-LVl were 3.6±5.7 and 0.9±1.4ml; CL_volume and count were 0.3±0.2ml and 7.2 ±8.3. TBSS showed widespread changes in DKI/DTI parameters. Significant changes were observed in MD, MK, FA, Daxon, AWF, and α. Significant correlations were found between CL_volume and CVLT (p<0.05), FAS (p<0.01), BVMT-FP (p<0.01); between MD_insula, FA_cingulate and CVLT (p<0.05); between α_forceps_minor, α_anterior thalamic radiation (ATR) and CLVT (p<0.05); between AWF_ATR, AWF_forceps_minor and DEFS_repetition (p<0.05) CONCLUSIONS: CL volume and DTI/DKI derived metrics allow a more comprehensive characterization of GM and WM damage in PP-MS patients and have cognitive impact Study Supported by: in part by Novartis Pharmaceuticals Disclosure: Dr. Petracca has nothing to disclose. Dr. Bender has nothing to disclose. Dr. Farrell has nothing to disclose. Dr. Teodorescu has nothing to disclose. Dr. Howard has nothing to disclose. Dr. Riley has received personal compensation for activities with Biogen Idec, EMD Serono, Pfizer Inc., Teva Neuroscience, and Bayer Pharmaceuticals Corp. Dr. Cahall has nothing to disclose. Dr. Arias has nothing to disclose. Dr. Fabian has received personal compensation for activities with Biogen Idec. as a speaker. Dr. Lublin has received personal compensation for activities with Biogen Idec, EMD Serono, Inc., Novartis, Teva Neuroscience, Actelion, Sanofi-Aventis Pharmaceuticals, Inc., Acorda Therapeutis, Questcor, Roche, Genentech, Inc., Celgene, Johnson & Johnson, Revalesio, Coronado Bioscience, Genzyme Corporation, MedImmune, Bristol-Myers Squibb Company, Xenoport, Receptos, Forward Pharma, and Osmotica. Dr. Lublin has received personal compensation in an editorial capacity for Multiple Sclerosis and Related Diseases. Dr. Lublin has received research support from Acorda Therapeutics, Inc., Biogen Idec, Novartis, Teva Neuroscience, Genzyme Corporation, Sanofi-Aventis Pharmaceuticals, Inc., Celgene, National Institutes of Health, and the National Multiple Sclerosis Society. Dr. Inglese has received research support from Novartis Pharmaceuticals.
OBJECTIVE: To investigate cortical and subcortical GM volume changes in patients with primary-pro... more OBJECTIVE: To investigate cortical and subcortical GM volume changes in patients with primary-progressive MS (PP-MS) over 6 and 12 months follow-up using high-field MRI. To assess the short-term predictive value and clinical relevance of MRI measures of GM atrophy. BACKGROUND: It has been shown that gray matter (GM) damage is more prominent in patients with progressive MS and that GM atrophy occurs at a faster pace than in patients with relapsing-remitting-MS. Thus, suggesting that measures of GM volume may be more sensitive to short-term disease progression than measures of clinical disability. DESIGN/METHODS: Brain MRI was acquired on a 3T scanner from 26 consecutive patients with PP-MS (14 F; mean±SD age:50.9±10.5 yrs; disease duration:8.1±4.4 yrs; median EDSS:4.0; range:1.5-6.0) at baseline, 6 months (20 patients) and 12 months (15 patients). The MRI protocol included: a) T2-W TSE; c) 3D T1-W. Normalized volumes of the whole brain (NBV), gray matter(GMV), white matter (WMV), thalamus and basal ganglia were measured at each time point using SIENA, SIENAX and FIRST. Correlations of baseline and changes in MRI parameters with EDSS, 25FWT, 9HPT, and SDMT were assessed using Spearman’s correlation coefficient test. RESULTS: Percentage volumetric changes(PVC) at month 6 and 12 relative to baseline were: (NBV:-.48±.72 and -.84±.89,GMW:-.24±1.68 and -.56±2.02;WMV:.41±2.18 and -.02±1.86; caudate:-.82±4.29 and -.06±4.74;putamen:-2.72±3.54 and -1.61±2.11;thalamus:-.78±2.14 and -1.75±3.04; Strong correlations were found between baseline thalamus and putamen volumes with SDMT (r=0.82,p<0.0001;r=0.58,p<0.03 respectively), adjusted for age and gender and between PVC in NBV and SDMT (r=-0.65,p<0.030) and 9HPT (r=0.66,p<0.03) over one year. CONCLUSIONS: Preliminary results from this ongoing study suggest that cortical and subcortical GM atrophy impact short-term cognitive and physical impairment in PP-MS patients. Study Supported by: Partially by Novartis Pharmaceuticals and National MS Society (grant number RG598589). M. P. is supported by a research fellowship grant from Fondazione Italiana Sclerosi Multipla (FISM cod. 2013/B/7). Disclosure: Dr. Ghassemi has nothing to disclose. AM received research support for participation in clinical trials from Acorda, Biogen Idec, Genentech, Genzyme/sanofi-aventis, Novartis, Questcor, and Roche. Dr. Krieger has received personal compensation for activities with Acorda Therapeutics, Bayer HealthCare, Biogen Idec, EMD Serono, Genzyme, Questcor Pharmaceuticals, and Teva Neuroscience as a consultant and/or advisory board member. Dr. Howard has nothing to disclose. Dr. Riley has received personal compensation for activities with Biogen Idec, Teva Pharmaceuticals, Novartis, and Genzyme as a consultant. Dr. Riley has received personal compensation in an editorial capacity for Multiple Sclerosis (The Resource Centre an Dr. Bencosome has nothing to disclose. Acorda Therapeutics, Inc.; Biogen Idec; Novartis Pharmaceuticals Corp; Teva Neuroscience, Inc.; Genzyme; Sanofi; Celgene; NIH; NMSS Dr. Inglese has received research support from Novartis Pharmaceuticals.
Importance: A robust cerebrospinal fluid (CSF) cell cryopreservation protocol using high resoluti... more Importance: A robust cerebrospinal fluid (CSF) cell cryopreservation protocol using high resolution single-cell (sc) transcriptomic data would enable the deployment of this important modality in multi-center translational research studies and clinical trials in which many sites do not have the expertise or resources to produce data from fresh samples. It would also serve to reduce technical variability in larger projects. Objective: To test a reliable cryopreservation protocol adapted for CSF cells, facilitating the characterization of these rare, fragile cells in moderate to large scale studies. Design: Diagnostic lumbar punctures were performed on twenty-one patients at two independent sites. Excess CSF was collected and cells were isolated. Each cell sample was split into two fractions for single cell analysis using one of two possible chemistries: 3′ sc-RNA-Sequencing or 5 ′ sc-RNA-Sequencing. One cell fraction was processed fresh while the second sample was cryopreserved and pr...
A 71-year-old woman previously on rituximab treatment for rheumatoid arthritis presented with 2 y... more A 71-year-old woman previously on rituximab treatment for rheumatoid arthritis presented with 2 years of progressive neurologic symptoms. She was found to have persistent hypogammaglobulinemia and B cell depletion despite rituximab discontinuation a year prior. MRI revealed diffuse meningeal enhancement along the entire neuroaxis. LP showed a CSF lymphocytic pleocytosis, elevated protein, and presence of enterovirus by PCR. The patient was hospitalized several times for progressive clinical and radiologic decline, though she had transient improvements following treatment with immunoglobulin therapy. Her CSF remained positive for enterovirus PCR for at least 12 months. Though two brain biopsies were non-diagnostic, pan- Enterovirus was ultimately identified using a high-throughput next-generation sequencing technique. She was treated with compassionate-use pocapavir with clinical stabilization at 4-month follow-up; however, she expired 8 months later from a bacterial pneumonia.
OBJECTIVE: To compare brain temperature between patients with relapsing-remitting (RR) and progre... more OBJECTIVE: To compare brain temperature between patients with relapsing-remitting (RR) and progressive courses of multiple sclerosis (MS). BACKGROUND: We recently reported elevated body temperature in RRMS relative to healthy individuals and progressive MS patients in the absence of exogenous heat exposure (Sumowski & Leavitt, 2014), an observation never before reported despite the long-standing literature describing negative consequences of experimental and environmental heat exposure in MS patients (i.e., Uhthoff’s phenomenon). Elevated body temperature may result from clinically-silent brain inflammation in RRMS. If so, brain temperature should also be elevated in RRMS patients. Here, we examined brain temperature in RRMS patients versus progressive MS. METHODS: We used MR spectroscopy to derive brain temperature in 14 patients (9 RRMS, 3 SPMS, 2 PPMS). MRS permits non-invasive measurement of brain temperature because hydrogen bonding is temperature-dependent; measuring the shift...
Objective: To conduct a randomized, double-blind crossover design pilot trial of aspirin as a pre... more Objective: To conduct a randomized, double-blind crossover design pilot trial of aspirin as a pretreatment to improve exercise performance in patients with multiple sclerosis (MS). Background: Exercise is only beneficial if people do it. Many MS patients are deterred from exercising by overheating and exhaustion (“Uhthoff’s phenomenon”). We tested aspirin, an antipyretic, to improve exercise performance and reduce exercise-induced body temperature increase in persons with MS. Design/Methods: Twelve MS patients participated. At enrollment, 8 of 12 participants reported heat-sensitivity. All participants completed two exercise sessions separated by one week. At each session, participants were administered a standard dose (650 mg) of aspirin or placebo. After one hour, participants performed a progressive ramped maximal exercise test (lower body cycle ergometer). Test was terminated when volitional exhaustion was reached. Paired samples t-tests were conducted to evaluate differences in...
Objective: To determine the effect of Natalizumab on the degree of inflammation after 3 and 6 mon... more Objective: To determine the effect of Natalizumab on the degree of inflammation after 3 and 6 months of treatment, using PK11195-PET. Background: The pathogenesis of MS is characterized by the influx of leukocytes from the periphery into the CNS, inducing a pro-inflammatory environment. This leads to stimulation of the innate immune system and causes subsequent microglia/macrophage activation. Natalizumab is a humanized antibody against the cell adhesion molecule alpha 4-integrin, preventing leukocytes from crossing endothelial borders. However, the effect of Natalizumab on the innate immune system is unknown. PK11195-PET is used to detect microglia/macrophage activation by binding translocator protein (TSPO), a protein found on the outer mitochondrial membrane of microglia/macrophages. Methods: For this longitudinal study 18 patients, starting Natalizumab, were included. PK11195-PET scans were acquired at baseline, 3 and 6 months post Natalizumab treatment. PK uptake was quantified...
The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a global... more The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a global effort to rapidly develop and deploy effective and safe coronavirus disease 2019 (COVID-19) vaccinations. Vaccination has been one of the most effective medical interventions in human history, although potential safety risks of novel vaccines must be monitored, identified, and quantified. Adverse events must be carefully assessed to define whether they are causally associated with vaccination or coincidence. Neurologic adverse events following immunizations are overall rare but with significant morbidity and mortality when they occur. Here, we review neurologic conditions seen in the context of prior vaccinations and the current data to date on select COVID-19 vaccines including mRNA vaccines and the adenovirus-vector COVID-19 vaccines, ChAdOx1 nCOV-19 (AstraZeneca) and Ad26.COV2.S Johnson & Johnson (Janssen/J&J).
Multiple Sclerosis Journal - Experimental, Translational and Clinical, 2020
We report a fatal case of COVID-19 in a 51-year-old African American woman with multiple sclerosi... more We report a fatal case of COVID-19 in a 51-year-old African American woman with multiple sclerosis on natalizumab. She had multiple risk factors for severe COVID-19 disease including race, obesity, hypertension, and elevated inflammatory markers, but the contribution of natalizumab to her poor outcome remains unknown. We consider whether altered dynamics of peripheral immune cells in the context of natalizumab treatment could worsen the cytokine storm syndrome associated with severe COVID-19. We discuss extended interval dosing as a risk-reduction strategy for multiple sclerosis patients on natalizumab, and the use of interleukin-6 inhibitors in such patients who contract COVID-19.
ObjectiveTo test the hypothesis that higher-challenge gait and balance tasks are more sensitive t... more ObjectiveTo test the hypothesis that higher-challenge gait and balance tasks are more sensitive than traditional metrics to subtle patient-reported gait dysfunction and future fall risk in early multiple sclerosis (MS).MethodsPersons with early MS (n = 185; ≤5 years diagnosed) reported gait function (MS Walking Scale) and underwent traditional disability metrics (Expanded Disability Status Scale [EDSS], Timed 25 Foot Walk). Patients and healthy controls (n = 50) completed clinically feasible challenge tasks of gait endurance (2-Minute Walk Test), standing balance (NIH Toolbox), and dynamic balance (balance boards; tandem walk on 2 ten-foot boards of different widths, 4.5 and 1.5 in). MRI assessed global and regional brain volumes, total T2 lesion volume (T2LV), infratentorial T2LVs and counts, and cervical cord lesion counts. Falls, near falls, and fall-related injuries were assessed after 1 year. We examined links between all tasks and patient-reported gait, MRI markers, and fall d...
Background: Persons with multiple sclerosis (MS) commonly report word-finding difficulty clinical... more Background: Persons with multiple sclerosis (MS) commonly report word-finding difficulty clinically, yet this language deficit remains underexplored. Objective: To investigate the prevalence and nature of word-finding difficulty in persons with early MS on three levels: patient report, cognitive substrates, and neuroimaging. Methods: Two samples of early MS patients ( n = 185 and n = 55; ⩽5 years diagnosed) and healthy controls ( n = 50) reported frequency/severity of cognitive deficits and underwent objective assessment with tasks of rapid automatized naming (RAN), measuring lexical access speed, memory, word generation, and cognitive efficiency. High-resolution brain magnetic resonance imaging (MRI) derived measurements of regional cortical thickness, global and deep gray matter volume, and T2 lesion volume. Relationships among patient-reported word-finding difficulty, cognitive performance, and neural correlates were examined. Results: Word-finding difficulty was the most common ...
Learning Objectives Upon completion of this activity, the participant will be able to: & Iden... more Learning Objectives Upon completion of this activity, the participant will be able to: & Identify normal anatomic landmarks on brain and spine MRIs & Formulate a differential diagnosis for lesions on brain and spine MRIs & Understand the limitations of current imaging techniques Address correspondence to Dr Riley Bove, University of California, San Francisco Sandler Neurosciences Center, 675 Nelson Rising Ln, San Francisco, CA 94158, Riley.Bove@ucsf.edu.
OBJECTIVE: 1) to measure cervical spinal cord (SC) atrophy in patients with primary-progressive m... more OBJECTIVE: 1) to measure cervical spinal cord (SC) atrophy in patients with primary-progressive multiple sclerosis (PP-MS); 2) to investigate the relationship between cervical SC atrophy and measures of brain volume, gray matter (GM) cortical lesion (CL) volume and count; 3) to determine the clinical impact of cervical SC atrophy. BACKGROUND: SC atrophy is a typical feature of PP-MS but the relationship with regional and global brain pathology especially in the GM is not well understood DESIGN/METHODS: As part of an ongoing study, s ixteen PP-MS patients (7M; mean age: 53.8±8.7; median EDSS: 4.0, range:1.5-6.0) and 16 age and gender matched CTRLs (7M; mean age: 53.0±9.2) underwent MRI at 3T. The MRI protocol included a) brain dual-echo; b) 3D T1-weighted; c) double inversion recovery (DIR); d) spine T2-weighted TSE; e) 3D T1-weighted.Normalized whole brain (NBV), white matter (WM) and GM volumes were measured as well as GM CL volume and count. Normalized cervical cord cross sectional area (CSAn) and spine volume (CSVn) was measured from C1 to C7 (total_CSAn and CSVn) and at C2 level (C2_CSVn). Between-group comparisons were assessed using a 2-sample t-test and the associations using Spearman’s rank correlation coefficient. RESULTS: NBV and GM volume, but not WM volume, were significantly lower in patients than in CTRLs (p 0.16±0.02 ml in patients and 0.23±0.01ml and 0.18±0.01ml in CTRLs (p 2 in patients and 74.6±6.4mm 2 in CTRLs (p<0.05). A trend of statistical significance was present between the C2_CSVn and the WM volume (p=0.06) and C2_CSVn and the left 9HPT (p=0.08); CONCLUSIONS: In PP-MS cord atrophy correlates with clinical disability and it is modestly associated with brain WM volume but not with GM brain and lesion load. Study Supported by: partially by Novartis Pharmaceuticals Disclosure: Dr. Teodorescu has nothing to disclose. Dr. Petracca has nothing to disclose. Dr. Farrell has nothing to disclose. Dr. Howard has nothing to disclose. Dr. Riley has received personal compensation for activities with Biogen Idec, EMD Serono, Pfizer Inc., Teva Neuroscience, and Bayer Pharmaceuticals Corp. Dr. Fabian has received personal compensation for activities with Biogen Idec. as a speaker. Dr. Lublin has received personal compensation for activities with Biogen Idec, EMD Serono, Inc., Novartis, Teva Neuroscience, Actelion, Sanofi-Aventis Pharmaceuticals, Inc., Acorda Therapeutis, Questcor, Roche, Genentech, Inc., Celgene, Johnson & Johnson, Revalesio, Coronado Bioscience, Genzyme Corporation, MedImmune, Bristol-Myers Squibb Company, Xenoport, Receptos, Forward Pharma, and Osmotica. Dr. Lublin has received personal compensation in an editorial capacity for Multiple Sclerosis and Related Diseases. Dr. Lublin has received research support from Acorda Therapeutics, Inc., Biogen Idec, Novartis, Teva Neuroscience, Genzyme Corporation, Sanofi-Aventis Pharmaceuticals, Inc., Celgene, National Institutes of Health, and the National Multiple Sclerosis Society. Dr. Inglese has received research support from Novartis Pharmaceuticals.
OBJECTIVE: 1) to characterize brain gray and white matter (GM, WM) injury in patients with primar... more OBJECTIVE: 1) to characterize brain gray and white matter (GM, WM) injury in patients with primary-progressive MS (PP-MS) using diffusional kurtosis imaging (DKI); 2) to investigate the associations between GM and WM DKI/DTI-derived parameters: mean diffusivity (MD), fractional anisotropy (FA), mean kurtosis (MK), axonal water fraction (AWF), tortuosity (ɑ), intraxonal diffusivity (D_axon) and cognitive impairment as measured by MACFIMS neuropsychological (NP) battery BACKGROUND: Although disability in PP-MS is believed to be predominantly due to spinal cord pathology, there is increasing evidence of cognition impairment. However, the underlying mechanisms are still not clear. DESIGN/METHODS: Sixteen PP-MS patients from an undergoing longitudinal study (7M; mean age: 53.8±8.7 yrs; median EDSS: 4.0) and 16 age and gender matched CTRLs (7M; mean age: 53.0±9.2 yrs) were administered the MACFIMS and underwent MRI at 3T. A twice-refocused EPI sequence (30 directions, voxel resolution 2mm3) was used for DKI/DTI. After DTI/DKI maps were derived voxelwise, TBSS was used for the analysis. In addition NBV, WM and GM volumes were measured as well as WM and GM cortical lesion (CL) volume and count. The between-group differences were determined with randomise function of FSL (p<0.05 TFCE-corrected). Associations with NP tests were assessed with Spearman’s correlation coefficient RESULTS: NBV and GM volume, but not WM volume, were significantly lower in patients than in CTRLs (p<0.05). T2-LV and T1-LVl were 3.6±5.7 and 0.9±1.4ml; CL_volume and count were 0.3±0.2ml and 7.2 ±8.3. TBSS showed widespread changes in DKI/DTI parameters. Significant changes were observed in MD, MK, FA, Daxon, AWF, and α. Significant correlations were found between CL_volume and CVLT (p<0.05), FAS (p<0.01), BVMT-FP (p<0.01); between MD_insula, FA_cingulate and CVLT (p<0.05); between α_forceps_minor, α_anterior thalamic radiation (ATR) and CLVT (p<0.05); between AWF_ATR, AWF_forceps_minor and DEFS_repetition (p<0.05) CONCLUSIONS: CL volume and DTI/DKI derived metrics allow a more comprehensive characterization of GM and WM damage in PP-MS patients and have cognitive impact Study Supported by: in part by Novartis Pharmaceuticals Disclosure: Dr. Petracca has nothing to disclose. Dr. Bender has nothing to disclose. Dr. Farrell has nothing to disclose. Dr. Teodorescu has nothing to disclose. Dr. Howard has nothing to disclose. Dr. Riley has received personal compensation for activities with Biogen Idec, EMD Serono, Pfizer Inc., Teva Neuroscience, and Bayer Pharmaceuticals Corp. Dr. Cahall has nothing to disclose. Dr. Arias has nothing to disclose. Dr. Fabian has received personal compensation for activities with Biogen Idec. as a speaker. Dr. Lublin has received personal compensation for activities with Biogen Idec, EMD Serono, Inc., Novartis, Teva Neuroscience, Actelion, Sanofi-Aventis Pharmaceuticals, Inc., Acorda Therapeutis, Questcor, Roche, Genentech, Inc., Celgene, Johnson & Johnson, Revalesio, Coronado Bioscience, Genzyme Corporation, MedImmune, Bristol-Myers Squibb Company, Xenoport, Receptos, Forward Pharma, and Osmotica. Dr. Lublin has received personal compensation in an editorial capacity for Multiple Sclerosis and Related Diseases. Dr. Lublin has received research support from Acorda Therapeutics, Inc., Biogen Idec, Novartis, Teva Neuroscience, Genzyme Corporation, Sanofi-Aventis Pharmaceuticals, Inc., Celgene, National Institutes of Health, and the National Multiple Sclerosis Society. Dr. Inglese has received research support from Novartis Pharmaceuticals.
OBJECTIVE: To investigate cortical and subcortical GM volume changes in patients with primary-pro... more OBJECTIVE: To investigate cortical and subcortical GM volume changes in patients with primary-progressive MS (PP-MS) over 6 and 12 months follow-up using high-field MRI. To assess the short-term predictive value and clinical relevance of MRI measures of GM atrophy. BACKGROUND: It has been shown that gray matter (GM) damage is more prominent in patients with progressive MS and that GM atrophy occurs at a faster pace than in patients with relapsing-remitting-MS. Thus, suggesting that measures of GM volume may be more sensitive to short-term disease progression than measures of clinical disability. DESIGN/METHODS: Brain MRI was acquired on a 3T scanner from 26 consecutive patients with PP-MS (14 F; mean±SD age:50.9±10.5 yrs; disease duration:8.1±4.4 yrs; median EDSS:4.0; range:1.5-6.0) at baseline, 6 months (20 patients) and 12 months (15 patients). The MRI protocol included: a) T2-W TSE; c) 3D T1-W. Normalized volumes of the whole brain (NBV), gray matter(GMV), white matter (WMV), thalamus and basal ganglia were measured at each time point using SIENA, SIENAX and FIRST. Correlations of baseline and changes in MRI parameters with EDSS, 25FWT, 9HPT, and SDMT were assessed using Spearman’s correlation coefficient test. RESULTS: Percentage volumetric changes(PVC) at month 6 and 12 relative to baseline were: (NBV:-.48±.72 and -.84±.89,GMW:-.24±1.68 and -.56±2.02;WMV:.41±2.18 and -.02±1.86; caudate:-.82±4.29 and -.06±4.74;putamen:-2.72±3.54 and -1.61±2.11;thalamus:-.78±2.14 and -1.75±3.04; Strong correlations were found between baseline thalamus and putamen volumes with SDMT (r=0.82,p<0.0001;r=0.58,p<0.03 respectively), adjusted for age and gender and between PVC in NBV and SDMT (r=-0.65,p<0.030) and 9HPT (r=0.66,p<0.03) over one year. CONCLUSIONS: Preliminary results from this ongoing study suggest that cortical and subcortical GM atrophy impact short-term cognitive and physical impairment in PP-MS patients. Study Supported by: Partially by Novartis Pharmaceuticals and National MS Society (grant number RG598589). M. P. is supported by a research fellowship grant from Fondazione Italiana Sclerosi Multipla (FISM cod. 2013/B/7). Disclosure: Dr. Ghassemi has nothing to disclose. AM received research support for participation in clinical trials from Acorda, Biogen Idec, Genentech, Genzyme/sanofi-aventis, Novartis, Questcor, and Roche. Dr. Krieger has received personal compensation for activities with Acorda Therapeutics, Bayer HealthCare, Biogen Idec, EMD Serono, Genzyme, Questcor Pharmaceuticals, and Teva Neuroscience as a consultant and/or advisory board member. Dr. Howard has nothing to disclose. Dr. Riley has received personal compensation for activities with Biogen Idec, Teva Pharmaceuticals, Novartis, and Genzyme as a consultant. Dr. Riley has received personal compensation in an editorial capacity for Multiple Sclerosis (The Resource Centre an Dr. Bencosome has nothing to disclose. Acorda Therapeutics, Inc.; Biogen Idec; Novartis Pharmaceuticals Corp; Teva Neuroscience, Inc.; Genzyme; Sanofi; Celgene; NIH; NMSS Dr. Inglese has received research support from Novartis Pharmaceuticals.
Uploads
Papers by Claire Riley