Publications by authors named "Joep Killestein"

162 Publications

B-Cell Depletion and COVID-19 Severity in Multiple Sclerosis: Remaining Challenges.

Neurology 2021 Oct 5. Epub 2021 Oct 5.

UCLA Dept. of Neurology, UCLA Multiple Sclerosis Program, Los Angeles, CA, USA.

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http://dx.doi.org/10.1212/WNL.0000000000012754DOI Listing
October 2021

Serum Neurofilament Light Association With Progression in Natalizumab-Treated Patients With Relapsing-Remitting Multiple Sclerosis.

Neurology 2021 Sep 9. Epub 2021 Sep 9.

Clinical Chemistry Laboratory, Amsterdam UMC.

ObjectiveThe objective of this study was to investigate the potential of serum neurofilament light (NfL) to reflect or predict progression mostly independent of acute inflammatory disease activity in patients with relapsing remitting multiple sclerosis (RRMS) treated with natalizumab.MethodsPatients were selected from a prospective observational cohort study initiated in 2006 at the VU University Medical Center Amsterdam, The Netherlands, including patients with RRMS treated with natalizumab. Selection criteria included an age of 18 years or older and a minimum follow-up of 3 years from natalizumab initiation. Clinical and MRI assessments were performedon a yearly basis, and serum NfL was measured at 5 time-points during the follow-up, including on the day of natalizumab initiation (baseline), 3 months, 1 year and 2 years after natalizumab initiation, and on last follow-up visit. Using general linear regression models, we compared the longitudinal dynamics of NfL between patients with and without confirmed EDSS progression between year 1 visit and last follow-up, and between individuals with and without EDSS progression, a composite endpoint including the EDSS, 9 hole peg test and timed 25 foot-walk.ResultsEighty-nine natalizumab-treated patients with RRMS were included. Median follow-up time was 5.2 years (IQR 4.3-6.7, range 3.0-11.0) after natalizumab initiation, mean age at time of natalizumab initiation was 36.9 (SD: 8.5), and median disease duration was 7.4 years (IQR 3.8-12.1). Between year 1 and the last follow-up, 28/89 (31.5%) individuals showed confirmed EDSS progression. Data for the EDSS endpoint was available for 73 out of the 89 patients and 35/73 (47.9%) showed confirmed EDSS progression.We observed a significant reduction in NfL levels 3 months after natalizumab initiation, which reached its nadir of close to 50% of baseline levels 1 year after treatment initiation. We found no difference in the longitudinal dynamics of NfL in progressors versus non-progressors. NfL levels at baseline and 1 year after natalizumab initiation did not predict progression at last follow-up.DiscussionIn our cohort of natalizumab-treated patients with RRMS, NfL fails to capture or predict progression that occurs largely independently of clinical or radiological signs of acute focal inflammatory disease activity. Additional biomarkers may thus be needed to monitor progression in these patients.Classification of EvidenceThis study provides Class II evidence that serum NfL levels are not associated with disease progression in natalizumab-treated patients with RRMS.
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http://dx.doi.org/10.1212/WNL.0000000000012752DOI Listing
September 2021

Loss of Neurologic Reserve in Progressive Multiple Sclerosis: A Paradigm Shift?

Neurol Clin Pract 2021 Aug;11(4):271-272

Amsterdam UMC (JK), Vrije Universiteit Amsterdam, Department of Neurology, MS Center Amsterdam, Amsterdam Neuroscience, the Netherlands; and National Research Council (CNR) (ML), Institute of Biomedical Technologies, Bari Unit, Italy.

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http://dx.doi.org/10.1212/CPJ.0000000000001106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382419PMC
August 2021

Pain, cognition and disability in advanced multiple sclerosis.

Scand J Pain 2021 Oct 2;21(4):754-765. Epub 2021 Sep 2.

Department of Neurology, OLVG location West, Amsterdam, The Netherlands.

Objectives: In patients with multiple sclerosis (MS), a relationship between physical disability and pain has been observed. In addition a relationship between physical disability and cognition in MS has been suggested. However, cognitive functions and pain appear not to be correlated in MS patients. Therefore, we examined whether a possible relationship between pain and cognitive functioning may exist, and if so, if such a relationship is mediated by physical disability.

Methods: Forty-five MS patients with chronic pain, and in an advanced stage of the disease were included. Physical disabilities were assessed by the Expanded Disability Status Scale (EDSS). Episodic memory was assessed by means of the Eight Words test, and Face and Picture Recognition. Executive functions (EF) were examined by Digit Span Backward for working memory, and the Rule Shift Cards and Category Fluency test for cognitive flexibility. Pain Intensity and Pain Affect were assessed by means of visual analogue scales and one verbal pain scale and mood (depression, anxiety) by the Beck Depression Inventory and the Symptom Check List (SCL-90). The research questions were analyzed by means of regression analyses and the Sobel test for mediation.

Results: A significant relationship was found between Pain Affect and EF, but that relationship was not mediated by physical disabilities (EDSS). In addition, Pain Intensity and EF showed a significant relationship but only in combination with physical disabilities (EDSS). Finally, mood was related to pain affect.

Discussion: The findings suggest that the lower the EF, exclusively or in combination with more physical disabilities, the more the patient may suffer from pain.

Implications: The more one is cognitively and physically impaired, the more one might suffer from pain, and, the less one is able to communicate pain. The latter could put MS patients at risk for underdiagnosing and undertreatment of pain.
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http://dx.doi.org/10.1515/sjpain-2021-0067DOI Listing
October 2021

Antibody development after COVID-19 vaccination in patients with autoimmune diseases in the Netherlands: a substudy of data from two prospective cohort studies.

Lancet Rheumatol 2021 Aug 6. Epub 2021 Aug 6.

Amsterdam Rheumatology and Immunology Center, location Reade, Department of Rheumatology, Amsterdam, Netherlands.

Background: Data are scarce on immunogenicity of COVID-19 vaccines in patients with autoimmune diseases, who are often treated with immunosuppressive drugs. We aimed to investigate the effect of different immunosuppressive drugs on antibody development after COVID-19 vaccination in patients with autoimmune diseases.

Methods: In this study, we used serum samples collected from patients with autoimmune diseases and healthy controls who were included in two ongoing prospective cohort studies in the Netherlands. Participants were eligible for inclusion in this substudy if they had been vaccinated with any COVID-19 vaccine via the Dutch national vaccine programme, which at the time was prioritising vaccination of older individuals. Samples were collected after the first or second COVID-19 vaccination. No serial samples were collected. Seroconversion rates and IgG antibody titres against the receptor-binding domain of the SARS-CoV-2 spike protein were measured. Logistic and linear regression analyses were used to investigate the association between medication use at the time of vaccination and at least until sampling, seroconversion rates, and IgG antibody titres. The studies from which data were collected are registered on the Netherlands Trial Register, Trial ID NL8513, and ClinicalTrials.org, NCT04498286.

Findings: Between April 26, 2020, and March 1, 2021, 3682 patients with rheumatic diseases, 546 patients with multiple sclerosis, and 1147 healthy controls were recruited to participate in the two prospective cohort studies. Samples were collected from patients with autoimmune diseases (n=632) and healthy controls (n=289) after their first (507 patients and 239 controls) or second (125 patients and 50 controls) COVID-19 vaccination. The mean age of both patients and controls was 63 years (SD 11), and 423 (67%) of 632 patients with autoimmune diseases and 195 (67%) of 289 controls were female. Among participants without previous SARS-CoV-2 infection, seroconversion after first vaccination were significantly lower in patients than in controls (210 [49%] of 432 patients 154 [73%] of 210 controls; adjusted odds ratio 0·33 [95% CI 0·23-0·48]; p<0·0001), mainly due to lower seroconversion in patients treated with methotrexate or anti-CD20 therapies. After the second vaccination, seroconversion exceeded 80% in all patient treatment subgroups, except among those treated with anti-CD20 therapies (three [43%] of seven patients). We observed no difference in seroconversion and IgG antibody titres between patients with a previous SARS-CoV-2 infection who had received a single vaccine dose (72 [96%] of 75 patients, median IgG titre 127 AU/mL [IQR 27-300]) and patients without a previous SARS-CoV-2 infection who had received two vaccine doses (97 [92%] of 106 patients, median IgG titre 49 AU/mL [17-134]).

Interpretation: Our data suggest that seroconversion after a first COVID-19 vaccination is delayed in older patients on specific immunosuppressive drugs, but that second or repeated exposure to SARS-CoV-2, either via infection or vaccination, improves humoral immunity in patients treated with immunosuppressive drugs. Therefore, delayed second dosing of COVID-19 vaccines should be avoided in patients receiving immunosuppressive drugs. Future studies that include younger patients need to be done to confirm the generalisability of our results.

Funding: ZonMw, Reade Foundation, and MS Center Amsterdam.
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http://dx.doi.org/10.1016/S2665-9913(21)00222-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346242PMC
August 2021

Safety, Patient-Reported Well-Being, and Physician-Reported Assessment of Walking Ability in Patients with Multiple Sclerosis for Prolonged-Release Fampridine Treatment in Routine Clinical Practice: Results of the LIBERATE Study.

CNS Drugs 2021 Sep 28;35(9):1009-1022. Epub 2021 Jul 28.

Department of Neurology, MS Center Amsterdam, Amsterdam UMC, VU Medical Center, Amsterdam, The Netherlands.

Background: Prolonged-release fampridine (PR-FAM) 10-mg tablet twice daily is the only approved pharmacological treatment for improvement of walking ability in adults with multiple sclerosis (MS). LIBERATE assessed the safety/effectiveness of PR-FAM in the real-world.

Objectives: The aim of this study was to collect additional safety data, including the incidence rate of seizures and other adverse events (AEs) of interest, from patients with MS taking PR-FAM in routine clinical practice (including patients aged ≥ 65 years and those with pre-existing cardiovascular risk factors). Other objectives included change over time in patient-reported evaluation of physical and psychological impact of MS while taking PR-FAM, and change over time in physician-reported assessment of walking ability in MS patients taking PR-FAM.

Methods: Patients with MS newly prescribed PR-FAM were recruited (201 sites, 13 countries). Demographic/safety data were collected at enrolment through 12 months. Physician-rated Clinical Global Impression of Improvement (CGI-I) scores for walking ability, and Multiple Sclerosis Impact Scale-29 (MSIS-29) were assessed.

Results: Safety analysis included 4646 patients with 3534.8 patient-years of exposure; median (range) age, 52.6 (21-85) years, 87.3% < 65 years, and 65.7% women. Treatment-emergent AEs (TEAEs) were reported in 2448 (52.7%) patients, and serious TEAEs were reported in 279 (6.0%) patients, of whom 37 (< 1%) experienced treatment-emergent serious AEs (TESAEs) considered related to PR-FAM. AEs of special interest (AESI) occurred in 1799 (38.7%) patients, and serious AESI in 128 (2.8%) patients. Seventeen (< 1%) patients experienced actual events of seizure. Overall, 1158 (24.9%) patients discontinued treatment due to lack of efficacy. At 12 months, a greater proportion of patients on-treatment had improvement from baseline in CGI-I for walking ability versus those who discontinued (61% vs. 11%; p <  0.001). MSIS-29 physical impact score improved significantly for patients on-treatment for 12 months versus those who discontinued (mean change, baseline to 12 months: - 9.99 vs. - 0.34 points; p <  0.001). Results were similar for MSIS-29 psychological impact.

Conclusion: No new safety concerns were identified in this real-world study, suggesting that routine risk-minimization measures are effective. CGI-I and MSIS-29 scores after 12 months treatment with PR-FAM treatment show clinical benefits consistent with those previously reported.

Trial Registration: ClinicalTrials.gov: NCT01480063.
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http://dx.doi.org/10.1007/s40263-021-00840-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408054PMC
September 2021

Serum Contactin-1 in CIDP: A Cross-Sectional Study.

Neurol Neuroimmunol Neuroinflamm 2021 07 20;8(5). Epub 2021 Jul 20.

From the Department of Neurology and Neurophysiology (L.W., C.V., F.E.), Amsterdam Neuroscience, Amsterdam UMC, Location AMC, Amsterdam, the Netherlands; Neuromuscular Diseases Unit (L.M.-A., C.L., L.Q.), Department of Neurology, Hospital de La Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Spain; Department of Clinical Neurosciences (J.F., S.R.), West Wing, John Radcliffe Hospital, Oxford, United Kingdom; Neurochemistry Lab (M.J.A.K.-S., C.E.T.), Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit, Amsterdam, the Netherlands; and Department of Neurology (M.C., Z.L., J.K.), Amsterdam Neuroscience, Amsterdam UMC, Location VU Medical Center, Amsterdam, the Netherlands.

Objective: To investigate whether serum levels of contactin-1, a paranodal protein, correlate with paranodal injury as seen in patients with CIDP with antibodies targeting the paranodal region.

Methods: Serum contactin-1 levels were measured in 187 patients with CIDP and 222 healthy controls. Paranodal antibodies were investigated in all patients.

Results: Serum contactin-1 levels were lower in patients (N = 41) with paranodal antibodies compared with patients (N = 146) without paranodal antibodies ( < 0.01) and showed good discrimination between these groups (area under the curve 0.84; 95% CI: 0.76-0.93).

Conclusions: These findings suggest that serum contactin-1 levels have the potential to serve as a possible diagnostic biomarker of paranodal injury in CIDP.

Classification Of Evidence: This study provides class II evidence that serum contactin-1 levels can discriminate between patients with CIDP with or without paranodal antibodies with a sensitivity of 71% (95% CI: 56%-85%) and a specificity of 97% (95% CI: 83%-100%).
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http://dx.doi.org/10.1212/NXI.0000000000001040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293285PMC
July 2021

Personalized B-cell tailored dosing of ocrelizumab in patients with multiple sclerosis during the COVID-19 pandemic.

Mult Scler 2021 Jul 9:13524585211028833. Epub 2021 Jul 9.

Department of Neurology, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

In this observational study, 159 patients with multiple sclerosis received personalized dosing of ocrelizumab incentivized by the COVID-19 pandemic. Re-dosing was scheduled when CD19 B-cell count was ⩾10 cells/µL (starting 24 weeks after the previous dose, repeated 4-weekly). Median interval until re-dosing or last B-cell count was 34 [30-38] weeks. No clinical relapses were reported and a minority of patients showed Expanded Disability Status Scale (EDSS) progression. Monthly serum neurofilament light levels remained stable during extended intervals. Two (1.9%) of 107 patients with a follow-up magnetic resonance imaging (MRI) scan showed radiological disease activity. Personalized dosing of ocrelizumab could significantly extend intervals with low short-term disease activity incidence, encouraging future research on long-term safety and efficacy.
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http://dx.doi.org/10.1177/13524585211028833DOI Listing
July 2021

The plasma peptides of Alzheimer's disease.

Clin Proteomics 2021 Jun 28;18(1):17. Epub 2021 Jun 28.

Ryerson Analytical Biochemistry Laboratory (RABL), Department of Chemistry and Biology, Faculty of Science, Ryerson University, 350 Victoria St., Toronto, ON, Canada.

Background: A practical strategy to discover proteins specific to Alzheimer's dementia (AD) may be to compare the plasma peptides and proteins from patients with dementia to normal controls and patients with neurological conditions like multiple sclerosis or other diseases. The aim was a proof of principle for a method to discover proteins and/or peptides of plasma that show greater observation frequency and/or precursor intensity in AD. The endogenous tryptic peptides of Alzheimer's were compared to normals, multiple sclerosis, ovarian cancer, breast cancer, female normal, sepsis, ICU Control, heart attack, along with their institution-matched controls, and normal samples collected directly onto ice.

Methods: Endogenous tryptic peptides were extracted from blinded, individual AD and control EDTA plasma samples in a step gradient of acetonitrile for random and independent sampling by LC-ESI-MS/MS with a set of robust and sensitive linear quadrupole ion traps. The MS/MS spectra were fit to fully tryptic peptides within proteins identified using the X!TANDEM algorithm. Observation frequency of the identified proteins was counted using SEQUEST algorithm. The proteins with apparently increased observation frequency in AD versus AD Control were revealed graphically and subsequently tested by Chi Square analysis. The proteins specific to AD plasma by Chi Square with FDR correction were analyzed by the STRING algorithm. The average protein or peptide log precursor intensity was compared across disease and control treatments by ANOVA in the R statistical system.

Results: Peptides and/or phosphopeptides of common plasma proteins such as complement C2, C7, and C1QBP among others showed increased observation frequency by Chi Square and/or precursor intensity in AD. Cellular gene symbols with large Chi Square values (χ2 ≥ 25, p ≤ 0.001) from tryptic peptides included KIF12, DISC1, OR8B12, ZC3H12A, TNF, TBC1D8B, GALNT3, EME2, CD1B, BAG1, CPSF2, MMP15, DNAJC2, PHACTR4, OR8B3, GCK, EXOSC7, HMGA1 and NT5C3A among others. Similarly, increased frequency of tryptic phosphopeptides were observed from MOK, SMIM19, NXNL1, SLC24A2, Nbla10317, AHRR, C10orf90, MAEA, SRSF8, TBATA, TNIK, UBE2G1, PDE4C, PCGF2, KIR3DP1, TJP2, CPNE8, and NGF amongst others. STRING analysis showed an increase in cytoplasmic proteins and proteins associated with alternate splicing, exocytosis of luminal proteins, and proteins involved in the regulation of the cell cycle, mitochondrial functions or metabolism and apoptosis. Increases in mean precursor intensity of peptides from common plasma proteins such as DISC1, EXOSC5, UBE2G1, SMIM19, NXNL1, PANO, EIF4G1, KIR3DP1, MED25, MGRN1, OR8B3, MGC24039, POLR1A, SYTL4, RNF111, IREB2, ANKMY2, SGKL, SLC25A5, CHMP3 among others were associated with AD. Tryptic peptides from the highly conserved C-terminus of DISC1 within the sequence MPGGGPQGAPAAAGGGGVSHRAGSRDCLPPAACFR and ARQCGLDSR showed a higher frequency and highest intensity in AD compared to all other disease and controls.

Conclusion: Proteins apparently expressed in the brain that were directly related to Alzheimer's including Nerve Growth Factor (NFG), Sphingomyelin Phosphodiesterase, Disrupted in Schizophrenia 1 (DISC1), the cell death regulator retinitis pigmentosa (NXNl1) that governs the loss of nerve cells in the retina and the cell death regulator ZC3H12A showed much higher observation frequency in AD plasma vs the matched control. There was a striking agreement between the proteins known to be mutated or dis-regulated in the brains of AD patients with the proteins observed in the plasma of AD patients from endogenous peptides including NBN, BAG1, NOX1, PDCD5, SGK3, UBE2G1, SMPD3 neuronal proteins associated with synapse function such as KSYTL4, VTI1B and brain specific proteins such as TBATA.
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http://dx.doi.org/10.1186/s12014-021-09320-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240224PMC
June 2021

Multiple sclerosis and drug discovery: A work of translation.

EBioMedicine 2021 Jun 24;68:103392. Epub 2021 May 24.

Department Anatomy and Neuroscience, Amsterdam University Medical Center (VUmc), Amsterdam, the Netherlands; MS-center Amsterdam (www.vumc.com), the Netherlands.

Multiple sclerosis (MS) is after trauma the most important neurological disease in young adults, affecting 1 per 1000 individuals. With currently available medications, most of these targeting the immune system, satisfactory results have been obtained in patients with relapsing MS, but these can have serious adverse effects. Moreover, despite some promising developments, such as with B cell targeting therapies or sphingosine-1-phosphate modulating drugs, there still is a high unmet need of safe drugs with broad efficacy in patients with progressive MS. Despite substantial investments and intensive preclinical research, the proportion of promising lead compounds that reaches the approved drug status remains disappointingly low. One cause lies in the poor predictive validity of MS animal models used in the translation of pathogenic mechanisms into safe and effective treatments for the patient. This disturbing situation has raised criticism against the relevance of animal models used in preclinical research and calls for improvement of these models. This publication presents a potentially useful strategy to enhance the predictive validity of MS animal models, namely, to analyze the causes of failure in forward translation (lab to clinic) via reverse translation (clinic to lab). Through this strategy new insights can be gained that can help generate more valid MS models.
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http://dx.doi.org/10.1016/j.ebiom.2021.103392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245896PMC
June 2021

SARS-CoV-2 Antibodies in Adult Patients With Multiple Sclerosis in the Amsterdam MS Cohort.

JAMA Neurol 2021 07;78(7):880-882

Department of Neurology, Amsterdam Neuroscience, Amsterdam MS Center, Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam, the Netherlands.

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http://dx.doi.org/10.1001/jamaneurol.2021.1364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087977PMC
July 2021

Tissue Transglutaminase Expression Associates With Progression of Multiple Sclerosis.

Neurol Neuroimmunol Neuroinflamm 2021 07 27;8(4). Epub 2021 Apr 27.

From Amsterdam UMC, Vrije Universiteit, Amsterdam Neuroscience, MS Center Amsterdam, Department of Anatomy and Neurosciences (C.S., M.D.S., J.J.P.B., M.M.M.W., B.D., A.-M.v.D.), Department of Neurology (C.E.L., J.K.), Department of Epidemiology and Biostatistics (J.W.R.T.), and Department of Clinical Chemistry (C.E.T.), Amsterdam, the Netherlands.

Objective: The clinical course of multiple sclerosis (MS) is variable and largely unpredictable pointing to an urgent need for markers to monitor disease activity and progression. Recent evidence revealed that tissue transglutaminase (TG2) is altered in patient-derived monocytes. We hypothesize that blood cell-derived TG2 messenger RNA (mRNA) can potentially be used as biomarker in patients with MS.

Methods: In peripheral blood mononuclear cells (PBMCs) from 151 healthy controls and 161 patients with MS, TG2 mRNA was measured and correlated with clinical and MRI parameters of disease activity (annualized relapse rate, gadolinium-enhanced lesions, and T2 lesion volume) and disease progression (Expanded Disability Status Scale [EDSS], normalized brain volume, and hypointense T1 lesion volume).

Results: PBMC-derived TG2 mRNA levels were significantly associated with disease progression, i.e., worsening of the EDSS over 2 years of follow-up, normalized brain volume, and normalized gray and white matter volume in the total MS patient group at baseline. Of these, in patients with relapsing-remitting MS, TG2 expression was significantly associated with worsening of the EDSS scores over 2 years of follow-up. In the patients with primary progressive (PP) MS, TG2 mRNA levels were significantly associated with EDSS, normalized brain volume, and normalized gray and white matter volume at baseline. In addition, TG2 mRNA associated with T1 hypointense lesion volume in the patients with PP MS at baseline.

Conclusion: PBMC-derived TG2 mRNA levels hold promise as biomarker for disease progression in patients with MS.

Classification Of Evidence: This study provides Class II evidence that in patients with MS, PBMC-derived TG2 mRNA levels are associated with disease progression.
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http://dx.doi.org/10.1212/NXI.0000000000000998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105890PMC
July 2021

Serum contactin-1 as a biomarker of long-term disease progression in natalizumab-treated multiple sclerosis.

Mult Scler 2021 Apr 23:13524585211010097. Epub 2021 Apr 23.

Department of Clinical Chemistry, Amsterdam UMC, Vrije Universiteit Amsterdam, Neurochemistry Laboratory and Biobank, Amsterdam Neuroscience, Amsterdam, The Netherlands.

Background: Natalizumab treatment provides a model for non-inflammation-induced disease progression in multiple sclerosis (MS).

Objective: To study serum contactin-1 (sCNTN1) as a novel biomarker for disease progression in natalizumab-treated relapsing-remitting MS (RRMS) patients.

Methods: Eighty-nine natalizumab-treated RRMS patients with minimum follow-up of 3 years were included. sCNTN1 was analyzed at baseline (before natalizumab initiation), 3, 12, 24 months (M) and last follow-up (median 5.2 years) and compared to 222 healthy controls (HC) and 15 primary progressive MS patients (PPMS). Results were compared between patients with progressive, stable, or improved disability according to EDSS-plus criteria.

Results: Median sCNTN1 levels (ng/mL,) in RRMS (baseline: 10.7, 3M: 9.7, 12M: 10.4, 24M: 10.8; last follow-up: 9.7) were significantly lower compared to HC (12.5; ⩽ 0.001). It was observed that 48% of patients showed progression during follow-up, 11% improved, and 40% remained stable. sCNTN1 levels were significantly lower in progressors both at baseline and at 12M compared to non-progressors. A 1 ng/mL decrease in baseline sCNTN1 was consistent with an odds ratio of 1.23 (95% confidence interval 1.04-1.45) ( = 0.017) for progression during follow-up.

Conclusion: Lower baseline sCNTN1 concentrations were associated with long-term disability progression during natalizumab treatment, making it a possible blood-based prognostic biomarker for RRMS.
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http://dx.doi.org/10.1177/13524585211010097DOI Listing
April 2021

Quelling Public Fears about Guillain-Barre Syndrome and COVID-19 Vaccination.

Neurology 2021 Apr 6. Epub 2021 Apr 6.

Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Neurology, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1212/WNL.0000000000011882DOI Listing
April 2021

Ultrasensitive immunoassay allows measurement of serum neurofilament heavy in multiple sclerosis.

Mult Scler Relat Disord 2021 May 10;50:102840. Epub 2021 Feb 10.

Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands; Department of Clinical Neurosciences, Neurology Unit, Geneva University Hospital, Geneva, Switzerland.

Background: Neurofilament heavy (NfH) is a promising biomarker for neuro-axonal damage in Multiple Sclerosis (MS). We compared the performance of high-sensitivity serum-NfH immunoassays, with as aim to investigate the value of serum-NfH as biomarker for MS.

Methods: We measured serum-NfH in 76 MS patients with Simoa (one commercial, one in-house) or Luminex assays. Serum-NfH measured by the immunoassay with greatest sensitivity was related to clinical and radiological outcomes with age and sex-adjusted linear regression analysis, and to biological outcomes cerebrospinal fluid (CSF)-NfH, serum neurofilament light (NfL) and CSF-NfL with Spearman's correlation analysis.

Results: With the commercial Simoa assay, we obtained 100% serum-NfH detectability (in-house Simoa: 70%, Luminex: 61%), with lowest coefficient of variation (CV) between duplicates of 11%CV (in-house Simoa: 22%CV, Luminex: 30%CV). Serum-NfH quantified with the commercial Simoa assay was associated with disease duration (standardized beta (sβ) = 0.28, p = 0.034), T2 lesion volume (sβ = 0.23, p = 0.041), and tended to associate with black hole count (sβ = 0.21, p = 0.084) but not with Expanded Disease Disability Score (EDSS) or normalized brain volume (all: p>0.10). Furthermore, serum-NfH showed correlations with CSF-NfH (rho = 0.27, p = 0.018) and serum-NfL (rho=0.44, p < 0.001), but not with CSF-NfL.

Conclusions: Serum-NfH can be quantified with high-sensitivity technology. Cross-sectionally, we observed some weak correlations of serum-NfH with MS disease burden parameters, suggesting there might be some utility for serum-NfH as biomarker for MS disease burden.
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http://dx.doi.org/10.1016/j.msard.2021.102840DOI Listing
May 2021

Varicella zoster-associated acute retinal necrosis and central nervous system complications in natalizumab treated MS patients.

Mult Scler Relat Disord 2021 May 10;50:102838. Epub 2021 Feb 10.

Department of Neurology, MS Center Amsterdam, Amsterdam UMC - location VUmc, Amsterdam, the Netherlands.

There is not much awareness of varicella zoster virus (VZV) associated central nervous system (CNS) infections under treatment with natalizumab. Here we describe two natalizumab treated MS patients who developed acute retinal necrosis combined with CNS vasculitis caused by VZV. In natalizumab treated patients, visual symptoms atypical of optic neuritis should be promptly evaluated by an ophthalmologist. Currently, a total of 12 cases of natalizumab-associated VZV CNS or retinal infections are reported in literature. Our two cases and overview of currently available data provide information on prognosis and treatment decisions of this rare but devastating complication.
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http://dx.doi.org/10.1016/j.msard.2021.102838DOI Listing
May 2021

Dynamic functional connectivity as a neural correlate of fatigue in multiple sclerosis.

Neuroimage Clin 2021 4;29:102556. Epub 2021 Jan 4.

Department of Anatomy and Neurosciences, Neuroscience Amsterdam, MS Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Background: More than 80% of multiple sclerosis (MS) patients experience symptoms of fatigue. MS-related fatigue is only partly explained by structural (lesions and atrophy) and functional (brain activation and conventional static functional connectivity) brain properties.

Objectives: To investigate the relationship of dynamic functional connectivity (dFC) with fatigue in MS patients and to compare dFC with commonly used clinical and MRI parameters.

Methods: In 35 relapsing-remitting MS patients (age: 42.83 years, female/male: 20/15, disease duration: 11 years) and 19 healthy controls (HCs) (age: 41.38 years, female/male: 11/8), fatigue was measured using the CIS-20r questionnaire at baseline and at 6-month follow-up. All subjects underwent structural and resting-state functional MRI at baseline. Global static functional connectivity (sFC) and dynamic functional connectivity (dFC) were calculated. dFC was assessed using a sliding-window approach by calculating the summed difference (diff) and coefficient of variation (cv) across windows. Moreover, regional connectivity between regions previously associated with fatigue in MS was estimated (i.e. basal ganglia and regions of the Default Mode Network (DMN): medial prefrontal, posterior cingulate and precuneal cortices). Hierarchical regression analyses were performed with forward selection to identify the most important correlates of fatigue at baseline. Results were not corrected for multiple testing due to the exploratory nature of the study.

Results: Patients were more fatigued than HCs at baseline (p = 0.001) and follow-up (p = 0.002) and fatigue in patients was stable over time (p = 0.213). Patients had significantly higher baseline global dFC than HCs, but no difference in basal ganglia-DMN dFC. In the regression model for baseline fatigue in patients, basal ganglia-DMN dFC-cv (standardized β = -0.353) explained 12.5% additional variance on top of EDSS (p = 0.032). Post-hoc analysis revealed higher basal ganglia-DMN dFC-cv in non-fatigued patients compared to healthy controls (p = 0.013), whereas fatigued patients and healthy controls showed similar basal ganglia-DMN dFC.

Conclusions: Less dynamic connectivity between the basal ganglia and the cortex is associated with greater fatigue in MS patients, independent of disability status. Within patients, lower dynamics of these connections could relate to lower efficiency and increased fatigue. Increased dynamics in non-fatigued patients compared to healthy controls might represent a network organization that protects against fatigue or signal early network dysfunction.
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http://dx.doi.org/10.1016/j.nicl.2020.102556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815811PMC
June 2021

The sequence of structural, functional and cognitive changes in multiple sclerosis.

Neuroimage Clin 2021 24;29:102550. Epub 2020 Dec 24.

Amsterdam UMC, Location VUmc, Departments of Radiology and Nuclear Medicine, MS Center Amsterdam, Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, The Netherlands. Electronic address:

Background: As disease progression remains poorly understood in multiple sclerosis (MS), we aim to investigate the sequence in which different disease milestones occur using a novel data-driven approach.

Methods: We analysed a cohort of 295 relapse-onset MS patients and 96 healthy controls, and considered 28 features, capturing information on T2-lesion load, regional brain and spinal cord volumes, resting-state functional centrality ("hubness"), microstructural tissue integrity of major white matter (WM) tracts and performance on multiple cognitive tests. We used a discriminative event-based model to estimate the sequence of biomarker abnormality in MS progression in general, as well as specific models for worsening physical disability and cognitive impairment.

Results: We demonstrated that grey matter (GM) atrophy of the cerebellum, thalamus, and changes in corticospinal tracts are early events in MS pathology, whereas other WM tracts as well as the cognitive domains of working memory, attention, and executive function are consistently late events. The models for disability and cognition show early functional changes of the default-mode network and earlier changes in spinal cord volume compared to the general MS population. Overall, GM atrophy seems crucial due to its early involvement in the disease course, whereas WM tract integrity appears to be affected relatively late despite the early onset of WM lesions.

Conclusion: Data-driven modelling revealed the relative occurrence of both imaging and non-imaging events as MS progresses, providing insights into disease propagation mechanisms, and allowing fine-grained staging of patients for monitoring purposes.
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http://dx.doi.org/10.1016/j.nicl.2020.102550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804841PMC
June 2021

Pharmacovigilance during treatment of multiple sclerosis: early recognition of CNS complications.

J Neurol Neurosurg Psychiatry 2021 02 23;92(2):177-188. Epub 2020 Nov 23.

Department of Radiology & Nuclear Medicine, MS Center Amsterdam, Neuroscience Amsterdam, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands.

An increasing number of highly effective disease-modifying therapies for people with multiple sclerosis (MS) have recently gained marketing approval. While the beneficial effects of these drugs in terms of clinical and imaging outcome measures is welcomed, these therapeutics are associated with substance-specific or group-specific adverse events that include severe and fatal complications. These adverse events comprise both infectious and non-infectious complications that can occur within, or outside of the central nervous system (CNS). Awareness and risk assessment strategies thus require interdisciplinary management, and robust clinical and paraclinical surveillance strategies. In this review, we discuss the current role of MRI in safety monitoring during pharmacovigilance of patients treated with (selective) immune suppressive therapies for MS. MRI, particularly brain MRI, has a pivotal role in the early diagnosis of CNS complications that potentially are severely debilitating and may even be lethal. Early recognition of such CNS complications may improve functional outcome and survival, and thus knowledge on MRI features of treatment-associated complications is of paramount importance to MS clinicians, but also of relevance to general neurologists and radiologists.
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http://dx.doi.org/10.1136/jnnp-2020-324534DOI Listing
February 2021

Tumor-Educated Platelet RNA for the Detection and (Pseudo)progression Monitoring of Glioblastoma.

Cell Rep Med 2020 Oct 20;1(7):100101. Epub 2020 Oct 20.

Brain Tumor Center Amsterdam, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center, Amsterdam, the Netherlands.

Tumor-educated platelets (TEPs) are potential biomarkers for cancer diagnostics. We employ TEP-derived RNA panels, determined by . We assessed specificity by comparing the spliced RNA profile of TEPs from glioblastoma patients with multiple sclerosis and brain metastasis patients (validation series, n = 157; accuracy, 80%; AUC, 0.81 [95% CI, 0.74-0.89; p < 0.001]). Second, analysis of patients with glioblastoma versus asymptomatic healthy controls in an independent validation series (n = 347) provided a detection accuracy of 95% and AUC of 0.97 (95% CI, 0.95-0.99; p < 0.001). Finally, we developed the digitalSWARM algorithm to improve monitoring of glioblastoma progression and demonstrate that the TEP tumor scores of individual glioblastoma patients represent tumor behavior and could be used to distinguish false positive progression from true progression (validation series, n = 20; accuracy, 85%; AUC, 0.86 [95% CI, 0.70-1.00; p < 0.012]). In conclusion, TEPs have potential as a minimally invasive biosource for blood-based diagnostics and monitoring of glioblastoma patients.
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http://dx.doi.org/10.1016/j.xcrm.2020.100101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576690PMC
October 2020

Response to letter 'Lymphocyte counts and the risk of COVID-19 in people with MS'.

Mult Scler 2021 09 16;27(10):1626-1627. Epub 2020 Oct 16.

Department of Neurology, Rijnstate Hospital, Arnhem, The Netherlands.

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http://dx.doi.org/10.1177/1352458520965468DOI Listing
September 2021

Mild progressive multifocal leukoencephalopathy after switching from natalizumab to ocrelizumab.

Neurol Neuroimmunol Neuroinflamm 2021 01 13;8(1). Epub 2020 Oct 13.

From the Department of Neurology (A.A.T., Z.Y.G.L., E.E.M.S., B.A.J., Z.L.E.K., J.K.), Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, MS Center Amsterdam; Department of Clinical Chemistry (C.E.T.), Neurochemistry Laboratory and Biobank, Amsterdam Neuroscience, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam; Department of Ophthalmology (A.P.), Neuro-ophthalmology Expertise Center, Amsterdam Neuroscience, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; Department of Diagnostic and Interventional Neuroradiology (M.P.W.), Hanover Medical School, Hanover, Germany; Department of Radiology and Nuclear Medicine (M.P.W., F.B.), Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, MS Center Amsterdam, the Netherlands; Department of Neuroinflammation (F.B.), Queen Square MS Centre, UCL Institute of Neurology, Faculty of Brain Sciences, University College London; and National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (F.B.), London, United Kingdom.

Objective: To describe the disease course of carryover progressive multifocal leukoencephalopathy (PML) after switching from natalizumab to ocrelizumab in 2 patients with relapsing-remitting MS.

Methods: Two case reports with 1 year of follow-up and retrospective longitudinal measurements of serum neurofilament light (NfL) levels and B-cells.

Results: PML was diagnosed 78 days (case 1) and 97 days (case 2) after discontinuation of natalizumab. Both patients developed mild immune reconstitution inflammatory syndrome (IRIS) despite B-cell depletion caused by ocrelizumab. NfL levels increased in both patients during PML-IRIS. PML-IRIS lesions stabilized after treatment with mefloquine and mirtazapine, followed by methylprednisolone, and both patients continued therapy with ocrelizumab when B-cells started to repopulate.

Conclusions: The clinical course of carryover PML was mild in both patients, suggesting that B-cell depletion possibly did not aggravate PML-IRIS in these 2 patients.
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http://dx.doi.org/10.1212/NXI.0000000000000904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577542PMC
January 2021

Blood platelet RNA enables the detection of multiple sclerosis.

Mult Scler J Exp Transl Clin 2020 Jul-Sep;6(3):2055217320946784. Epub 2020 Jul 30.

Department of Neurology, Neuroscience Amsterdam, VUmc MS Center Amsterdam, Amsterdam UMC, VU University Medical Center, Amsterdam, The Netherlands.

Background: In multiple sclerosis (MS), clinical assessment, MRI and cerebrospinal fluid are important in the diagnostic process. However, no blood biomarker has been confirmed as a useful tool in the diagnostic work-up.

Objectives: Blood platelets contain a rich spliced mRNA repertoire that can alter during megakaryocyte development but also during platelet formation and platelet circulation. In this proof of concept study, we evaluate the diagnostic potential of spliced blood platelet RNA for the detection of MS.

Methods: We isolated and sequenced platelet RNA of blood samples obtained from 57 MS patients and 66 age- and gender-matched healthy controls (HCs). 60% was used to develop a particle swarm-optimized (PSO) support vector machine classification algorithm. The remaining 40% served as an independent validation series.

Results: In total, 1249 RNAs with differential spliced junction expression levels were identified between platelets of MS patients as compared to HCs, including EPSTI1, IFI6, and RPS6KA3, in line with reported inflammatory signatures in the blood of MS patients. The RNAs were subsequently used as input for a MS classifier, capable of detecting MS with 80% accuracy in the independent validation series.

Conclusions: Spliced platelet RNA may enable the blood-based diagnosis of MS, warranting large-scale validation.
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http://dx.doi.org/10.1177/2055217320946784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418262PMC
July 2020

Vaccination in B-cell-depleted patients with multiple sclerosis.

Neurology 2020 10 29;95(14):613-614. Epub 2020 Jul 29.

From the Department of Neurology (J.K.), MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, the Netherlands; Department of Clinical Neurosciences (R.D.P.), Service of Neurology, Lausanne University Hospital and University of Lausanne, Switzerland; Department of Neurology (B.H.), School of Medicine, Technical University of Munich; and Munich Cluster for Systems Neurology (B.H.), Munich, Germany.

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http://dx.doi.org/10.1212/WNL.0000000000010378DOI Listing
October 2020

Personalized extended interval dosing of natalizumab in MS: A prospective multicenter trial.

Neurology 2020 08 20;95(6):e745-e754. Epub 2020 Jul 20.

From the Department of Neurology, Amsterdam MS Center (Z.L.E.v.K., B.W.v.O., B.M.J.U., J.K.), Department of Radiology (M.P.W., F.B.), and Neurochemistry Lab and Biobank, Department of Clinical Chemistry (C.E.T.), Amsterdam Neuroscience, and Department of Epidemiology and Biostatistics (B.I.L.-W.), Amsterdam University Medical Centers, Vrije Universiteit; Department of Neurology (E.L.J.H.), St. Antonius Hospital, Utrecht, the Netherlands; Department of Diagnostic and Interventional Neuroradiology (M.P.W.), Hannover Medical School, Germany; Department of Neurology (N.F.K.), OLVG Hospital, Amsterdam; Department of Neurology (J.P.M.), Rijnstate Hospital, Arnhem; Biologics Lab, Bioanalysis (A.d.V.), Sanquin Diagnostic Services; Department of Immunopathology (A.t.B., T.R.), Sanquin Research, Amsterdam; Landsteiner Laboratory (A.t.B., T.R.), Academic Medical Centre, University of Amsterdam, the Netherlands; and UCL Institutes of Neurology & Healthcare Engineering (F.B.), Queen Square, London, UK.

Objective: To determine whether natalizumab efficacy is maintained when switching to personalized extended interval dosing based on individual natalizumab trough concentrations in patients with relapsing-remitting multiple sclerosis (RRMS).

Methods: This was a prospective multicenter single-arm trial with 1 year follow-up and a 1-year extension phase. Participants were adult persons with RRMS treated with natalizumab without disease activity in the year prior to enrollment. The natalizumab treatment interval was based on longitudinal natalizumab trough concentrations. Patients received 3 monthly MRI scans, relapse assessments, and disability scoring during follow-up. The primary endpoint was the occurrence of gadolinium-enhancing lesions on MRI. Secondary endpoints were new/enlarging T2 lesions on MRI and relapses and progression on the Expanded Disability Status Scale (EDSS) during follow-up and extension phase.

Results: Sixty-one patients were included. Eighty-four percent extended the interval from a 4-week interval to a 5- to 7-week interval. No patient developed gadolinium-enhancing lesions (95% confidence interval [CI] 0%-7.4%) during follow-up. No new/enlarging T2 lesions (95% CI 0%-7.4%) or relapses (95% CI 0%-7.4%) were reported during follow-up and in the extension phase. Median EDSS was comparable at baseline (3.0, interquartile range [IQR] 2.0-5.0) and after follow-up (3.0, IQR 2.0-5.0).

Conclusion: Personalized extended interval dosing did not induce recurrence of MS disease activity. Natalizumab efficacy was maintained in stable patients with RRMS receiving personalized extended interval dosing based on individual natalizumab concentrations.

Classification Of Evidence: This study provides Class IV evidence that personalized extended interval dosing of natalizumab does not result in recurrence of disease activity in stable patients with RRMS.
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http://dx.doi.org/10.1212/WNL.0000000000009995DOI Listing
August 2020

COVID-19 in multiple sclerosis: The Dutch experience.

Mult Scler 2020 09 14;26(10):1256-1260. Epub 2020 Jul 14.

Department of Neurology, Rijnstate Hospital, Arnhem, The Netherlands.

Here, we provide an extensive overview of all reported COVID-19 cases in multiple sclerosis (MS) patients in the Netherlands between 27 February and 9 June 2020, gathered by the Dutch MS Taskforce of the Netherlands Society of Neurology. A total of 86 MS patients were reported, 43 of whom tested positive for COVID-19. Of 43 patients who tested positive, 22 patients were hospitalized. Three intensive care unit (ICU) admissions and four deaths were reported. Our findings show no apparent difference in disease-modifying treatment (DMT) use and COVID-19 disease course in Dutch MS patients. In addition, a clear link between low lymphocyte count and severe disease was not observed.
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http://dx.doi.org/10.1177/1352458520942198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493197PMC
September 2020

4-aminopyridine is not just a symptomatic therapy, it has a neuroprotective effect - Yes.

Mult Scler 2020 10 6;26(11):1309-1310. Epub 2020 Jul 6.

Department of Neurology, MS Center Amsterdam, Amsterdam UMC, Location VUmc, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1177/1352458520923951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543014PMC
October 2020

Clinico-radiological dissociation of disease activity in MS patients: frequency and clinical relevance.

J Neurol 2020 Nov 20;267(11):3287-3291. Epub 2020 Jun 20.

Department of Radiology and Nuclear Medicine, Amsterdam UMC, Location VU University Medical Center, Amsterdam, The Netherlands.

Objective: To investigate the prevalence and clinical relevance regarding disability progression in multiple sclerosis patients with a dissociation in clinical and radiological disease expression.

Methods: We prospectively selected patients with early relapsing-remitting multiple sclerosis (MS) or a clinically isolated syndrome (CIS) from the Amsterdam MS cohort. Patients underwent clinical examination at baseline, after 2 years, 6 years and a subset also after 11 years, including the Expanded Disability Status Scale (EDSS), 25-foot walk test (25-FWT) and 9-hole peg test (9-HPT). Brain and spinal cord MRI scans were obtained at baseline and after 2 years. Two years after baseline, patients with dissociation in their clinical and radiological disease progression were identified as: (1) patients with high clinical disease activity (defined by relapses) and low radiological disease activity (defined by white-matter lesions on T2-weighted imaging); or (2) patients with low clinical disease activity and high radiological disease activity. Binary logistic regression analyses were performed to predict disability progression after 6 and 11 years of follow-up. Patients with low clinical and low radiological disease activity were used as the reference group.

Results: The prevalence of clinico-radiological dissociation was low (6.4% had high clinical and low radiological disease activity and 5.1% had a combination of low clinical and high radiological disease activity) compared to 88.5% of patients without a dissociation. Patients with a dissociation of clinical and radiological disease activity did not show a statistically significant difference in risk of disability progression after 6 and 11 years.

Conclusions: A clinico-radiological dissociation is rather a rare phenomenon in MS patients. The clinical relevance of such a dissociation regarding the prediction of disability progression is questionable.
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http://dx.doi.org/10.1007/s00415-020-09991-1DOI Listing
November 2020
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