B cell depletion therapy does not resolve chronic active multiple sclerosis lesions.

BACKGROUND: Chronic active lesions (CAL) in multiple sclerosis (MS) have been observed even in patients taking high-efficacy disease-modifying therapy, including B-cell depletion. Given that CAL are a major determinant of clinical progression, including progression independent of relapse activity (PIRA), understanding the predicted activity and real-world effects of targeting specific lymphocyte populations is critical for designing next-generation treatments to mitigate chronic inflammation in MS. METHODS: We analyzed published lymphocyte single-cell transcriptomes from MS lesions and bioinformatically predicted the effects of depleting lymphocyte subpopulations (including CD20 B-cells) from CAL via gene-regulatory-network machine-learning analysis. Motivated by the results, we performed in vivo MRI assessment of PRL changes in 72 adults with MS, 46 treated with anti-CD20 antibodies and 26 untreated, over ∼2 years. FINDINGS: Although only 4.3% of lymphocytes in CAL were CD20 B-cells, their depletion is predicted to affect microglial genes involved in iron/heme metabolism, hypoxia, and antigen presentation. In vivo, tracking 202 PRL (150 treated) and 175 non-PRL (124 treated), none of the treated paramagnetic rims disappeared at follow-up, nor was there a treatment effect on PRL for lesion volume, magnetic susceptibility, or T1 time. PIRA occurred in 20% of treated patients, more frequently in those with ≥4 PRL (p = 0.027). INTERPRETATION: Despite predicted effects on microglia-mediated inflammatory networks in CAL and iron metabolism, anti-CD20 therapies do not fully resolve PRL after 2-year MRI follow up. Limited tissue turnover of B-cells, inefficient passage of anti-CD20 antibodies across the blood-brain-barrier, and a paucity of B-cells in CAL could explain our findings. FUNDING: Intramural Research Program of NINDS, NIH; NINDS grants R01NS082347 and R01NS082347; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Cariplo Foundation (grant #1677), FRRB Early Career Award (grant #1750327); Fund for Scientific Research (FNRS).

Cognitive trajectories in relapsing-remitting multiple sclerosis: Evidence of multiple evolutionary trends.

BACKGROUND: Cognitive impairment (CI) frequently occurs in multiple sclerosis (MS) and is assumed to increase over time. However, recent studies have suggested that the evolution of cognitive status in patients with MS may be more heterogeneous than expected. Predicting CI remains also challenging, and longitudinal studies exploring the baseline determinants of cognitive performances are limited. No studies have explored the predictive value of patient-reported outcome measures (PROMs) regarding future CI. OBJECTIVE: To explore the evolutionary patterns of cognitive status in a cohort of RRMS patients initiating a new disease modifying treatment (DMT), and to determine whether PROMs may have a predictive value for future CI. METHODS: The present prospective study is a 12-month follow-up of a cohort of 59 RRMS patients who underwent yearly a comprehensive, multiparametric assessment combining clinical (with EDSS assessment), neuropsychological (BVMT-R, SDMT, CVLT-II), MRI-derived metrics and a set of self-reported questionnaires. Lesion and brain volumes were analyzed and processed by the automated MSmetrix® software (Icometrix®, Leuven, Belgium). Spearman's correlation coefficient was used to evaluate the association of collected variables. A longitudinal logistic regression analysis was performed to find baseline correlates of CI at 12 months (T1). RESULTS: A total of 33 patients (56%) were defined as cognitively impaired at baseline, and 20 (38%) were defined as impaired at follow-up after 12 months. The mean raw scores and Z-scores of all the cognitive tests were significantly improved at T1 (p < 0.05). There was a statistically significant improvement in most PROM scores at T1 (p < 0.05) in comparison with baseline scores. Among the variables assessed, lower education and physical disability level at baseline correlated with impaired SDMT (OR: 1.68, p = 0.01; OR: 3.10, p = 0.02, respectively) and impaired BVMT-R (OR: 4.08, p=<0.001; OR: 4.82, p = 0.001, respectively) at T1. Neither baseline PROMs nor MRI volumetric parameters were predictive of cognitive performances at T1. CONCLUSIONS: These findings provide additional evidence that evolution of CI in MS may be a dynamic phenomenon and will not usually follow an inevitable, declining trajectory, and do not support the utility of PROMs in predicting CI in RRMS. The present study is still ongoing to determine whether our findings are confirmed at 2 and 3 years of follow-up.

Patient-reported outcome measurements in a selective cohort of relapsing-remitting multiple sclerosis patients: relationships with physical disability, cognitive impairment, and MRI-derived metrics.

BACKGROUND: The added value of patient-reported outcome measures (PROMs) in addition to standard clinical outcome tools in the assessment of relapsing-remitting multiple sclerosis (RRMS) patients' status is increasingly recognized. PROMs facilitate the detection of hidden aspects of MS and help to integrate the patient's subjective experience of health-related quality of life (HRQoL) status and treatment satisfaction in a holistic way. However, the relationship between PROMs and clinical and cognitive status has been scarcely investigated up to now. OBJECTIVE: To investigate the association of PROMs with physical and cognitive disability in a cohort of RRMS patients at initiation of a new disease-modifying treatment. METHODS: In this cross-sectional bicenter study, 59 consecutive RRMS patients underwent neurological examination with EDSS assessment, comprehensive cognitive tests (BVMT-R, SDMT, CVLT-II) and a set of self-reported questionnaires. Lesion and brain volumes were analyzed and processed by the automated MSmetrix® software (Icometrix®, Leuven, Belgium). Spearman's correlation coefficient was used to evaluate the association of collected variables. A cross-sectional logistic regression analysis was performed to find baseline correlates of cognitive impairment. RESULTS: Of the 59 RRMS patients (mean age 39 ± 9.8 years, 79.7% female, median EDSS 2.0), 33 (56%) had cognitive impairment. While almost all dimensions of health, explored by PROMs, were impacted in the overall sample, no significant difference was observed in patients with and without cognitive impairment. All PROMs were significantly associated with EDSS (R = 0.37-0.55; p < 0.05), except for the psychological component of MSIS-29, BDI and DEX-Q scores. No significant correlation was found between PROMs and cognitive performances. The cross-sectional logistic regression analysis included age, gender (female), education, EDSS, hippocampus and FLAIR lesion volumes as significant predictors of cognitive impairment. CONCLUSIONS: The data highlight that PROMs provide valuable information on the well-being of PwMS closely paralleling the extent of MS-related disability, as measured by the EDSS. Additional research should determine the relevance of PROMs as longitudinal outcome measures.

Relapsing-remitting Optic Neuropathy in an HIV-infected Patient: Secondary Auto-immune Optic Neuropathy or Infectious Optic Neuropathy? A Case Report and Review of the Literature.

It can be challenging to disentangle human immunodeficiency virus (HIV)-related infectious optic neuropathy and secondary triggered auto-immune disease when an HIV positive patient presents with vision loss. We report a 44-year-old untreated HIV positive Congolese woman who presented with two episodes of vision loss associated with pain in first her left eye and then her right eye and was diagnosed with a relapsing optic neuropathy. A correlation was observed between the clinical activity and cerebrospinal fluid viral load, CD4-count in the blood and magnetic resonance imaging signs of blood - optic nerve barrier breakdown. CD4 cell counts and viral loads are great clinical features to identify the type of acute optic neuropathy since differential diagnosis between an infectious optic neuropathy or an auto-immune induced optic neuropathy such as neuromyelitis optica spectrum disorder or immune reconstitution inflammatory syndrome can be puzzling.

Effects of prolonged-release fampridine on multiple sclerosis-related gait impairments. A crossover, double-blinded, placebo-controlled study.

BACKGROUND: People with multiple sclerosis have reduced walking speed and impaired gait pattern. Prolonged release-fampridine is a potassium channel blocker that improves nerve conduction in patients with multiple sclerosis, leading to walking benefits. Whether fampridine alters gait pattern is unknown. METHODS: In this crossover, randomized controlled trial, patients with multiple sclerosis were tested for responder status during a 4-week run-in period. Patients were considered responders if they improved their 25-ft walk test by 10% and improved their perceived walking capacity. Responders were randomized to prolonged release-fampridine (10 mg b.i.d.) or placebo for a 6-week period. After a 2-week wash-out period, they were allocated to the other treatment for 6 weeks. Participants were assessed before and after both conditions. Three-dimensional gait analysis assessed kinematic, kinetic, mechanic and energetic variables while walking on a treadmill at comfortable speed. Six-minute walk test and 25-ft walk test were used to assess walking speed on middle and short-distances, respectively. Patient-reported outcome measures were also used. Repeated measures ANCOVAs were applied to assess the treatment effects. FINDINGS: Out of 39 included patients, 24 responders (12 women; Expanded Disability Status Scale:4.25[4-5]; age:46 ± 10 years; maximal speed:0.93 ± 0.38 m·s-1) were identified. Among them, prolonged release-fampridine reduced the external mechanical work (-0.039 J·kg-1·m-1;p = 0.02), and improved knee flexion during swing phase (+5.3°; p = 0.02). No differences were found in other walking tests and patient-reported outcomes, at group-level. INTERPRETATION: Prolonged release-fampridine increases knee flexion during swing phase and lowers mechanical external work. Whether these changes are related to clinically meaningful improvements in walking capacity and other functional variables should be further investigated.

Immune-mediated neurological syndromes in SARS-CoV-2-infected patients.

BACKGROUND: Evidence of immune-mediated neurological syndromes associated with the severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection is limited. We therefore investigated clinical, serological and CSF features of coronavirus disease 2019 (COVID-19) patients with neurological manifestations. METHODS: Consecutive COVID-19 patients with neurological manifestations other than isolated anosmia and/or non-severe headache, and with no previous neurological or psychiatric disorders were prospectively included. Neurological examination was performed in all patients and lumbar puncture with CSF examination was performed when not contraindicated. Serum anti-gangliosides antibodies were tested when clinically indicated. RESULTS: Of the 349 COVID-19 admitted to our center between March 23rd and April 24th 2020, 15 patients (4.3%) had neurological manifestations and fulfilled the study inclusion/exclusion criteria. CSF examination was available in 13 patients and showed lymphocytic pleocytosis in 2 patients: 1 with anti-contactin-associated protein 2 (anti-Caspr2) antibody encephalitis and 1 with meningo-polyradiculitis. Increased serum titer of anti-GD1b antibodies was found in three patients and was associated with variable clinical presentations, including cranial neuropathy with meningo-polyradiculitis, brainstem encephalitis and delirium. CSF PCR for SARS-CoV-2 was negative in all patients. CONCLUSIONS: In SARS-Cov-2 infected patients with neurological manifestations, CSF pleocytosis is associated with para- or post-infectious encephalitis and polyradiculitis. Anti-GD1b and anti-Caspr2 autoantibodies can be identified in certain cases, raising the question of SARS-CoV-2-induced secondary autoimmunity.

Telecommunication and rehabilitation for patients with multiple sclerosis: access and willingness to use. A cross-sectional study.

BACKGROUND: Telerehabilitation is a promising approach for patients with multiple sclerosis (MS), but uncertainties regarding patients' access and preferences remain. AIM: To investigate the access to telecommunication technologies and rehabilitation services of patients with MS, and their willingness to use these technologies for rehabilitation. DESIGN: Cross-sectional survey. SETTING: Outpatient neurological facility. POPULATION: Patients with MS. METHODS: Patients with MS attending consultations in the Neurology department were asked to fill in a paper questionnaire. This anonymous z was designed to gain information about needs and access to rehabilitation and telecommunication technologies, as well as interests and perspectives of telerehabilitation among these patients. Descriptive statistics, Chi-squared tests and logistic regressions were used to describe the sample and survey answers. RESULTS: Two hundred patients completed the questionnaire. Mean age was 44.41(±12.52) years. Seventy-one percent were women, and 49% were unemployed. Ninety-one percent of the patients regularly used internet and 73% used apps. Most patients were interested in using telecommunication technologies to receive a program of physical exercises (62%), for information and personalized advice about physical activity and MS (69%), and to communicate with caregivers (75%). Patients with EDSS>4 were less interested than patients with EDSS≤4 in communicating with the caregivers via apps (33% vs. 52%,Δ19%[CI-36%;-2%],P=0.04) but expressed greater interest in receiving information and personal advice about physical activity and MS via the internet (70% vs. 51%,Δ19%[CI+2%;+36%],P=0.03). One third of the patients was not interested in receiving telerehabilitation interventions (32%), notably patients with EDSS>4 and non-workers. CONCLUSIONS: Patients with MS are mainly interested in using telecommunication technologies for rehabilitation services, and most of these patients have access to the required technology. Being mildly disabled and having a professional activity are associated with a greater interest in telerehabilitation. In contrary, patients with moderate-to-severe disability and non-workers have reportedly less access and ease in using the required technologies. CLINICAL REHABILITATION IMPACT: Telerehabilitation is feasible and wished by patients with MS, specifically in patients with low EDSS scores and workers. Given the strong need for rehabilitation in more disabled patients, the barriers to its access, the lower access and ease of use of telecommunication technologies, a special effort is needed to facilitate their use in these patients.

Improvement in progressive multifocal leukoencephalopathy after pembrolizumab-induced immune reconstruction inflammatory syndrome in a patient with follicular lymphoma.

Progressive multifocal leukoencephalopathy (PML) may develop in follicular lymphoma patients treated with bendamustine-rituximab. In this report, treatment with pembrolizumab successfully inhibited the clinical progression of PML by promoting radiologically demonstrated immune restoration inflammatory syndrome (IRIS), allowing complete clearance of the virus. These findings may further support the use of pembrolizumab in PML with special consideration for the potential occurrence of IRIS.

Effects of Fampridine in People with Multiple Sclerosis: A Systematic Review and Meta-analysis.

BACKGROUND: Prolonged-release (PR) fampridine is a potassium channel blocker used as a symptomatic treatment for walking disability in patients with multiple sclerosis (MS). Its clinical effects in such patients have not been systematically reviewed, and may be more wide-ranging than expected. OBJECTIVES: To summarize the evidence on the effects of PR fampridine in patients with MS. METHODS: A systematic search of Pubmed, Scopus (including EMBASE), and PsycINFO (completed in 01/2019) was carried out to identify randomized controlled trials (RCT) that compared PR fampridine to placebo. When appropriate, data were pooled using a random-effects model, and standardized mean differences (SMD) were computed. Study quality was assessed using the Downs and Black checklist. PRISMA guidelines were followed. All retrieved functional outcomes were categorized according to the International Classification of Functioning, Disability and Health (ICF). RESULTS: A total of 706 articles were screened for inclusion. Twenty RCTs involving 2616 patients met the eligibility criteria. Most studies were of good-to-excellent quality. PR fampridine administration resulted in significant benefits in relation to walking short distances (SMD: 1.23 (95% IC 0.65-1.81)) and perceived walking capacity (0.64 (0.27-1.02)). Its effects on muscle strength and middle-distance walking were not significant (0.53 (- 0.04 to 1.10) and 0.31 (- 0.18 to 0.80), respectively). No effect on higher-level cognitive functions (- 0.07 (- 0.58 to 0.45)) or hand and arm use (0.16 (- 0.33 to 0.64)) was observed. Individual studies reported effects on other outcomes across the ICF domains. CONCLUSIONS: There is strong evidence that PR fampridine exerts strong effects on the ability to walk short distances and on perceived walking capacity. Other effects of PR fampridine according to the ICF are possible but still unclear.

Timed Up-and-Go and 2-Minute Walk Test in patients with multiple sclerosis with mild disability: reliability, responsiveness and link with perceived fatigue.

BACKGROUND: Mobility limitations are frequent in patients with multiple sclerosis (MS), and could already be present in patients with so-called mild neurological disability (Expanded Disability Status Scale≤4). Assessing mobility in these patients is therefore of paramount importance. Timed Up-and-Go Test (TUG) and 2-Minute Walk Test (2MWT) are two clinically feasible tests which reliability and responsiveness are unknown among these patients. Whether fatigue, which is the number one symptom among these patients, is linked to these limitations remains unknown. AIM: The aim of this study was to explore the intrarater reliability and minimal detectable change (MDC95), as an index of responsiveness, of TUG and 2MWT. To explore their link with perceived fatigue among patients with MS. DESIGN: Cross-sectional observational study, including two measures. SETTING: Two university hospital outpatient centers. POPULATION: Patients (N.=63, 49 seen twice) with MS with mild disability (Expanded Disability Status Scale≤4). METHODS: 2MWT and TUG were performed twice in one occasion, and repeated 2 weeks later. Modified fatigue impact scale (MFIS) was used to assess fatigue. Intraclass coefficient correlations were calculated for immediate and 2-week reliability. MDC95 were computed. Correlations between mobility indices and fatigue were explored using Spearman's ρ. RESULTS: Mobility was impaired in comparison to normative values (2MWT: -4.9% from normative distance; TUG: +32% from normative time). The immediate reliability was excellent for both the 2MWT (ICC=0.98) and TUG (ICC=0.98). Reliability at 2 weeks was excellent for 2MWT (ICC=0.95) and very good for TUG (ICC=0.90). MDC95 were respectively 20m (2MWT) and 1.3s (TUG). Both measures were significantly weakly correlated to total MFIS (ρ=-0.37 and 0.39, respectively; P<0.01). CONCLUSIONS: The 2MWT and TUG are highly reliable and responsive in the assessment of respectively the walking capacity and general mobility of patients with MS with mild disability. Mobility impairments are linked to perceived fatigue among these patients. CLINICAL REHABILITATION IMPACT: TUG and 2MWT are easy to administer and could be reliably used in so called mildly disabled patients with MS to assess mobility limitation.

Thyroid disorders in alemtuzumab-treated multiple sclerosis patients: a Belgian consensus on diagnosis and management.

This paper deals with thyroid disease that can occur after treatment with alemtuzumab (humanized monoclonal anti-CD52) for relapsing-remitting multiple sclerosis (MS). The 5-year incidence of thyroid adverse events in phase 3 clinical trials is up to 40.7%. In most cases, the thyroid dysfunction is mild and easily manageable and only few serious thyroid adverse events have been reported. The need for patient education on the risk of thyroid dysfunction, as well as regular clinical and biochemical thyroid function screening is well described. However, practical clinical guidance in case of abnormal thyroid-related findings prior to or after alemtuzumab treatment is currently lacking. Therefore, a Belgian taskforce consisting of MS and thyroid experts was created in 2016, with the objective of issuing a clinical thyroid management algorithm based on available scientific evidence and personal experience with regard to alemtuzumab treatment-related thyroid adverse events.

Long-term safety and real-world effectiveness of fingolimod in relapsing multiple sclerosis.

With a growing number of disease-modifying therapies becoming available for relapsing multiple sclerosis, there is an important need to gather real-world evidence data regarding long-term treatment effectiveness and safety in unselected patient populations. Although not providing as high a level of evidence as randomized controlled trials, and prone to bias, real-world studies from observational studies or registries nevertheless provide crucial information on real-world outcomes of a given therapy. In addition, evaluation of treatment satisfaction and impact on quality of life are increasingly regarded as complementary outcome measures. Fingolimod was the first oral disease-modifying therapy approved for relapsing multiple sclerosis. This review aims to summarize current knowledge on the long-term effectiveness and safety outcomes of multiple sclerosis patients on fingolimod. Impact on treatment satisfaction and quality of life will be discussed according to available data.

Fatigue and physical fitness of mildly disabled persons with multiple sclerosis: a cross-sectional study.

Fatigue is frequent and disabling in persons with multiple sclerosis (pwMS) with mild neurological disability. These patients also have impaired physical fitness. Whether mildly disabled pwMS are deconditioned, and this deconditioning is linked to fatigue, remains unknown. Our aim is to determine the physical fitness of mildly disabled patients with multiple sclerosis and study its relationship with perceived fatigue and to link perceived fatigue with other parameters. Twenty patients (14 women; mean age: 45.5 years) with mild disability (Expanded Disability Status Scale 0-4) underwent a 2-min walking test, Timed Up-and-Go test, aerobic capacity testing, and isometric knee extension testing to assess strength and neuromuscular fatigability. They completed questionnaires assessing perceived fatigue, psychological status, and physical activity. Correlation coefficients and multivariate regression were used to analyze the relationships among variables. Seventeen (85%) patients reported a high level of fatigue. Thirteen (65%) patients had subnormal aerobic capacity. Fatigue was weakly to moderately associated with aerobic capacity, mobility, walking capacity, depression, and neuromuscular fatigability. An association of disease duration, aerobic capacity, and the neuromuscular fatigability index explained 65.1% of fatigue. A high proportion of pwMS with mild neurological disability are fatigued and deconditioned. Perceived fatigue is linked to aerobic capacity, neuromuscular fatigability, depression, mobility, and walking capacity. Focusing on these parameters could help in the management of fatigue.

Early disturbances in multimodal evoked potentials as a prognostic factor for long-term disability in relapsing-remitting multiple sclerosis patients.

OBJECTIVE: The aim of this study was to investigate whether early alterations in evoked potentials (EPs) have a prognostic value in relapsing-remitting multiple sclerosis (RRMS). METHODS: We retrospectively selected 108 early MS patients with a neurological follow-up ranging from 5 to 15years, in whom multimodal EPs (visual, brainstem auditory, somatosensory and motor) were performed at diagnosis. A conventional ordinal score was used to quantify the observed abnormalities. RESULTS: The extent of change in the composite EP score was well correlated to the Expanded Disability Status Scale (EDSS) at ten years (Y10) and up to 15years (Y11-15) after disease onset. Analysis of the predictive value of the EP score showed an increased risk of disability progression at Y10 and Y11-15 of 60% (p<0.0001) and 73% (p<0.0001) respectively in patients with an EP score >4. Conversely, the risk of disability progression at Y10 and Y11-15 associated with a lower EP score (⩽4) was reduced to 16% and 20% respectively. CONCLUSIONS: Our data support the good predictive value for long-term disability progression of multimodal EPs performed early after disease onset in RRMS patients. SIGNIFICANCE: This study, performed in a homogeneous RRMS cohort with long term follow-up, demonstrates the value of an early comprehensive neurophysiological assessment as a marker for future disability.

Anti-N-methyl-D-aspartate receptor encephalitis with favorable outcome despite prolonged status epilepticus.

BACKGROUND: To describe a case of auto-immune encephalitis in an adolescent with favorable outcome despite prolonged status epilepticus. METHODS: A 17 year old Asian man without previous medical history developed alteration of consciousness and partial seizures. The diagnosis of anti-N-methyl-D-aspartate receptor encephalitis was confirmed by the detection of specific antibodies in both cerebrospinal fluid and serum. RESULTS: The clinical course was complicated by prolonged status epilepticus which was refractory to a large number of antiepileptic drugs, including barbiturate coma. Immunomodulatory therapy included steroids, plasma exchanges, and intravenous immunoglobulins. After 86 days of intensive therapy, the patient regained consciousness progressively. Brain magnetic resonance imaging never demonstrated any lesion. Extensive search for a tumor was negative. At 12 month follow-up, the patient had made an excellent recovery. CONCLUSION: Auto-immune encephalitis is likely underdiagnosed in adolescents. In their most severe presentation, seizures may be resistant to a large number of anti-epileptic drugs, and the clinical improvement seems to be mainly because of the immunomodulatory therapy. Relapse is possible, as well as the delayed development of a teratoma or other tumor.

Correlation between tap test and CSF aqueductal stroke volume in idiopathic normal pressure hydrocephalus.

INTRODUCTION: The diagnosis and management of idiopathic normal pressure hydrocephalus (INPH) remains unclear despite the development of guidelines. In addition, the role of cerebrospinal fluid (CSF) aqueductal stroke volume (ASV) remains unspecified. OBJECTIVES: The aim of this study was to compare the results of the tap test (TT) and ASV in patients with possible INPH. MATERIALS AND METHODS: Among 21 patients investigated with both TT and phase-contrast (PC) MRI, we identified two groups, with either (1) a positive TT (PTT) or (2) a negative one (NTT), and we compared their ASV as measured by PC-MRI. ASV cutoff value was set at 70 µL/cardiac cycle (mean value +2 standard deviations in age-matched healthy subjects). RESULTS: In the PTT group (n = 9), the mean ASV was 175 ± 71 µL. Among these patients, four were shunted, and improved after surgery. In the NTT group, two patients were finally diagnosed with aqueductal stenosis and excluded. Among the remaining patients (n = 10), the mean ASV was 96 ± 93 µL (p < 0.05). However, three of these patients presented with hyperdynamic ASV, and an associated neurodegenerative disorder was diagnosed. Two patients had ventriculoperitoneal shunting despite their NTT, and improved. DISCUSSION/CONCLUSIONS: In our patient population, the noninvasive measurement of hyperdynamic ASV correlated with PTT, suggesting PC-MRI could be utilized to select those patients who would benefit from shunting. ASV may therefore be an interesting supplemental diagnosis tool.