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  • 1
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    Online Resource
    Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity
    Proceedings of the National Academy of Sciences ; 2021
    In:  Proceedings of the National Academy of Sciences Vol. 118, No. 1 ( 2021-01-05)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 118, No. 1 ( 2021-01-05)
    Abstract: Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies ( n NationMS = 946, n BIONAT = 990). Additionally, effect-modification by medication and photosensitivity-associated MC1R variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-β–treated patients. In carriers of MC1R :rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2018457118
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2021
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    detail.hit.zdb_id: 1461794-8
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  • 2
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    Axonal damage determines clinical disability in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): A prospective cohort study of different CIDP subtypes and disease stages
    Wiley ; 2022
    In:  European Journal of Neurology Vol. 29, No. 2 ( 2022-02), p. 583-592
    Details
    In: European Journal of Neurology, Wiley, Vol. 29, No. 2 ( 2022-02), p. 583-592
    Abstract: Monitoring of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is challenging in daily medical practice because the interrelationship between clinical disability, CIDP subtype, and neuronal degeneration is still elusive. The aim of this prospective cohort study was to investigate the role of different electrophysiological variables in CIDP monitoring. Methods Comprehensive bilateral nerve conduction studies (NCS) and structured clinical examinations were performed in 95 patients with typical CIDP and CIDP variants (age at inclusion 58.6 ± 11.6 years; median [range] inflammatory neuropathy cause and treatment overall disability score (INCAT‐ODSS) 3 [0–9] ), at time of first diagnosis in 25 of these patients (based on data from the prospective Immune‐mediated Neuropathies Biobank registry). After 12 months, 33 patients underwent follow‐up examination. Typical CIDP patients and patients with CIDP variants were characterized electrophysiologically and each individual NCS variable and the overall sum score for axonal damage and demyelination were then correlated to clinical disability scores (INCAT‐ODSS, modified Medical Research Council (MRS) sum score, and INCAT sensory score). Results As opposed to demyelination markers, the NCS axonal damage variable correlated strongly with disability at both first diagnosis and advanced disease stages in cross‐sectional and longitudinal analyses. Distal compound muscle action potential amplitudes of the upper limbs were found to have the strongest correlation with overall clinical function. Typical and atypical CIDP variants had distinct electrophysiological characteristics but, in typical CIDP, axonal degeneration markers were more strongly associated with clinical disability. Conclusions Total disability is largely determined by the degree of axonal damage, especially in typical CIDP. Although most patients have symptoms predominantly in the legs, NCS of the upper limbs are essential for the monitoring of patients with CIDP and CIDP variants.
    Type of Medium: Online Resource
    ISSN: 1351-5101 , 1468-1331
    URL: Issue
    URL: Article
    DOI: 10.1111/ene.v29.2
    DOI: 10.1111/ene.15156
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2020241-6
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  • 3
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    Dose-dependent immunomodulatory effects of bortezomib in experimental autoimmune neuritis
    Oxford University Press (OUP) ; 2021
    In:  Brain Communications Vol. 3, No. 4 ( 2021-10-01)
    Details
    In: Brain Communications, Oxford University Press (OUP), Vol. 3, No. 4 ( 2021-10-01)
    Abstract: Proteasome inhibition with bortezomib has been reported to exert an immunomodulatory action in chronic autoimmune neuropathies. However, bortezomib used for the treatment of multiple myeloma induces a painful toxic polyneuropathy at a higher concentration. Therefore, we addressed this controversial effect and evaluated the neurotoxic and immunomodulatory mode of action of bortezomib in experimental autoimmune neuritis. Bortezomib-induced neuropathy was investigated in Lewis rats using the von Frey hair test, electrophysiological, qPCR and histological analyses of the sciatic nerve as well as dorsal root ganglia outgrowth studies. The immunomodulatory potential of bortezomib was characterized in Lewis rats after experimental autoimmune neuritis induction with P253-78 peptide. Clinical, electrophysiological, histological evaluation, von Frey hair test, flow cytometric and mRNA analyses were used to unravel the underlying mechanisms. We defined the toxic concentration of 0.2 mg/kg bortezomib applied intraperitoneally at Days 0, 4, 8 and 12. This dosage induces a painful toxic neuropathy but preserves axonal regeneration in vitro. Bortezomib at a concentration of 0.05 mg/kg significantly ameliorated experimental autoimmune neuritis symptoms, improved experimental autoimmune neuritis-induced hyperalgesia and nerve conduction studies, and reduced immune cell infiltration. Furthermore, proteasome inhibition induced a transcriptional downregulation of Nfkb in the sciatic nerve, while its inhibitor Ikba (also known as Nfkbia) was upregulated. Histological analyses of bone marrow tissue revealed a compensatory increase of CD138+ plasma cells. Our data suggest that low dose bortezomib (0.05 mg/kg intraperitoneally) has an immunomodulatory effect in the context of experimental autoimmune neuritis through proteasome inhibition and downregulation of nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NFKB). Higher bortezomib concentrations (0.2 mg/kg intraperitoneally) induce sensory neuropathy; however, the regeneration potential remains unaffected. Our data empathizes that bortezomib may serve as an attractive treatment option for inflammatory neuropathies in lower concentrations.
    Type of Medium: Online Resource
    ISSN: 2632-1297
    URL: Article
    DOI: 10.1093/braincomms/fcab238
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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  • 4
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    Correlates of polyneuropathy in Parkinson’s disease
    Wiley ; 2020
    In:  Annals of Clinical and Translational Neurology Vol. 7, No. 10 ( 2020-10), p. 1898-1907
    Details
    In: Annals of Clinical and Translational Neurology, Wiley, Vol. 7, No. 10 ( 2020-10), p. 1898-1907
    Abstract: Previous studies in Parkinson’s disease (PD) patients have demonstrated a high prevalence of polyneuropathy (PNP) and pronounced alpha‐Synuclein pathology in dermal nerve fibers already at early disease stages. The aim of this study was to analyze associations between the prevalence and severity of PNP with nonmotor and motor symptoms in PD patients. Methods Fifty PD patients were characterized comprehensively for the presence of clinical symptoms (nonmotor and motor), electrophysiologic alterations and – for the first time – using high‐resolution ultrasound of peripheral nerves. Results Sixty‐two percent of PD patients showed electrophysiological pathology of PNP. The prevalence of patient‐reported PNP symptoms was 86% and was particularly present in patients with longer disease duration, compromised scores of nonmotor and motor symptoms as well as with a negative evaluation of quality of life. Seventy‐five percent of patients showed morphologic alterations similar to axonal PNP in high‐resolution ultrasound compared to healthy controls. Interpretation The study demonstrates the high burden of peripheral nervous system disease in Parkinson's disease. It advocates further studies to delineate the underlying pathophysiological mechanisms in order to optimize treatment approaches for PD, including the associated PNP.
    Type of Medium: Online Resource
    ISSN: 2328-9503 , 2328-9503
    URL: Issue
    URL: Article
    DOI: 10.1002/acn3.v7.10
    DOI: 10.1002/acn3.51182
    Language: English
    Publisher: Wiley
    Publication Date: 2020
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  • 5
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    Treatment response to cyclophosphamide, rituximab, and bortezomib in chronic immune-mediated sensorimotor neuropathies: a retrospective cohort study
    SAGE Publications ; 2021
    In:  Therapeutic Advances in Neurological Disorders Vol. 14 ( 2021-01), p. 175628642199963-
    Details
    In: Therapeutic Advances in Neurological Disorders, SAGE Publications, Vol. 14 ( 2021-01), p. 175628642199963-
    Abstract: Up to 20% of patients with chronic immune-mediated sensorimotor neuropathies (CIN) do not respond adequately to first-line therapies. However, studies on further treatment are scarce. Methods: We analyzed retrospectively 200 CIN patients regarding disease characteristics and response to therapy with cyclophosphamide (CYP), rituximab (RTX), and bortezomib (BTZ). Treatment response was defined as improvement or stabilization of inflammatory neuropathy cause and treatment overall disability score (INCAT-ODSS). Results: A total of 48 of 181 patients (26.5%) received therapy with CYP, RTX, or BTZ. The most frequently and first used therapy was CYP (69%). More than 40% of patients needed a second or third treatment. Overall, 71 treatments were applied in 48 patients. The combination of up to all three treatments enhanced the response-rate to 90%. Treatment within 24 months after initial diagnosis resulted in significantly higher response rate than late treatment (79% versus 50 %, p = 0.04, χ 2 -test, n = 46) and in lower disability in long-term follow up (INCAT-ODSS 3.8 versus 5.8, p = 0.02, t-test, n = 48). Patients with Lewis-Sumner syndrome ( n = 9) and autoantibody mediated neuropathies ( n = 13) had excellent response rates after treatment with RTX (90–100%). In contrast, typical chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) showed a response rate of 64% in CYP, 64% in RTX, and 75% in BTZ. Conclusion: Treatment with CYP, RTX, or BTZ was effective in this cohort of CIN refractory to first-line treatment. Our data increase evidence for an early use of these therapies. High efficacy of RTX in Lewis-Sumner syndrome in contrast to typical CIDP suggests a distinct pathophysiology.
    Type of Medium: Online Resource
    ISSN: 1756-2864 , 1756-2864
    URL: Article
    DOI: 10.1177/1756286421999631
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2021
    detail.hit.zdb_id: 2442245-9
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  • 6
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    Vagal cross-sectional area correlates with parasympathetic dysfunction in Parkinson's disease
    Oxford University Press (OUP) ; 2022
    In:  Brain Communications Vol. 5, No. 1 ( 2022-12-29)
    Details
    In: Brain Communications, Oxford University Press (OUP), Vol. 5, No. 1 ( 2022-12-29)
    Abstract: The aim of this prospective study was to investigate autonomic function in Parkinson’s disease with a multidimensional approach including clinical evaluation tools, head-up tilt test and morphological studies of the vagus nerve. Head-up tilt test parameters including high frequency power of the heart frequency interval, the ratio of low frequency power of the distance between two consecutive R waves in electrocardiogram (RR interval) to the high frequency and low frequency power of systolic blood pressure were used to evaluate parasympathetic, cardiac sympathetic and vasomotor sympathetic functions, respectively, in 80 patients with Parkinson's disease. We examined the cross-sectional area of the vagus nerves bilaterally using nerve ultrasound and compared mean values with a control group of healthy subjects (n = 40) as well as patients with chronic inflammatory demyelinating polyneuropathy (n = 76). The cross-sectional area of right/left vagus nerve of Parkinson's patients was significantly lower compared to the right/left vagus nerve of the control group and of chronic demyelinating polyneuropathy patients. Furthermore, the cross-sectional area of the right vagus nerve was significantly larger from the one of the left vagus nerve for all groups. Based on tilt test, 43 patients (disease duration 7 ± 5, age at evaluation 71 ± 9, Hoehn and Yahr score 2.8 ± 8) were diagnosed with autonomic dysfunction (orthostatic hypertension n = 11, chronotropic incompetence n = 31, postural orthostatic tachycardia syndrome n = 1). Patients with orthostatic hypotension showed significantly higher Unified Parkinson’s Disease Rating Scale-III values than those with chronotropic incompetence. The cross-sectional area of the vagus nerve correlated inversely with heart rate in rest and supine position and positively with tilt test parameters representing parasympathetic modulation through vagal activity [high frequency power of the distance between two consecutive R waves in electrocardiogram (RR interval)] at rest. We demonstrate for the first time that morphological characteristics of the vagus nerve correlate with parameters of parasympathetic function from the spectral analysis of cardiovascular parameters in tilt test for Parkinson's patients. This correlation reveals the impact of the atrophy of vagal atrophy for autonomic function in Parkinson's disease. Nerve ultrasound of the vagus nerve could potentially be used as an adjunct to tilt table examination to diagnose autonomic dysfunction.
    Type of Medium: Online Resource
    ISSN: 2632-1297
    URL: Article
    DOI: 10.1093/braincomms/fcad006
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 7
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    New Approaches to Critical Illness Polyneuromyopathy: High-Resolution Neuromuscular Ultrasound Characteristics and Cytokine Profiling
    Springer Science and Business Media LLC ; 2021
    In:  Neurocritical Care Vol. 35, No. 1 ( 2021-08), p. 139-152
    Details
    In: Neurocritical Care, Springer Science and Business Media LLC, Vol. 35, No. 1 ( 2021-08), p. 139-152
    Abstract: Diagnosis of intensive care unit acquired weakness (ICUAW) is challenging. Pathogenesis of underlying critical illness polyneuromyopathy (CIPNM) remains incompletely understood. This exploratory study investigated whether longitudinal neuromuscular ultrasound examinations and cytokine analyses in correlation to classical clinical and electrophysiological assessment contribute to the understanding of CIPNM. Methods Intensive care unit patients were examined every 7 days until discharge from hospital. Clinical status, nerve conduction studies, electromyography as well as ultrasound of peripheral nerves and tibial anterior muscle were performed. Cytokine levels were analyzed by a bead-based multiplex assay system. Results Of 248 screened patients, 35 patients were included at median of 6 days (IQR: 8) after admission to intensive care unit. Axonal damage was the main feature of CIPNM. At the peak of CIPNM (7 days after inclusion), nerve ultrasound showed cross-sectional area increase of tibial nerve as a sign of inflammatory edema as well as hypoechoic nerves as a possible sign of inflammation. Cytokine analyses showed signs of monocyte and macrophage activation at this stage. Fourteen days after inclusion, cytokines indicated systemic immune response as well as profiles associated to neovascularization and regeneration. Conclusions Exploratory neuromuscular ultrasound and cytokine analyses showed signs of inflammation like macrophage and monocyte activation at the peak of CIPNM followed by a systemic immune response parallel to axonal damage. This underlines the role of both axonal damage and inflammation in pathogenesis of CIPNM.
    Type of Medium: Online Resource
    ISSN: 1541-6933 , 1556-0961
    URL: Article
    DOI: 10.1007/s12028-020-01148-2
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
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  • 8
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    Report of a fulminant anti‐ pan‐neurofascin ‐associated neuropathy responsive to rituximab and bortezomib
    Wiley ; 2021
    In:  Journal of the Peripheral Nervous System Vol. 26, No. 4 ( 2021-12), p. 475-480
    Details
    In: Journal of the Peripheral Nervous System, Wiley, Vol. 26, No. 4 ( 2021-12), p. 475-480
    Abstract: Inflammatory neuropathies with pathogenic involvement of the nodes of Ranvier through autoantibodies have been increasingly characterized in the past years. The so‐called anti‐pan‐NF‐associated neuropathies caused by the simultaneous existence of anti‐Neurofascin‐186/‐140 and ‐155‐antibodies are extremely rare and cause life‐threatening symptoms. Therapeutic strategies are needed as symptoms may be life‐threatening and may not respond to standard first‐line CIDP treatment. We report a case of a 52‐year‐old male with a rare anti‐pan‐neurofascin (NF) (‐155, ‐186/‐140)‐associated neuropathy. The initial presentation was subacute with mild paresthesia leading to a fulminant “locked‐in”‐like syndrome requiring mechanical ventilation within the first eight weeks despite treatment with intravenous immunoglobulins. Nerve conduction studies revealed non‐excitable nerves with acute spontaneous activity in electromyography. High titers of anti‐Neurofascin‐155, −186/−140‐antibodies were detected in serum and cerebrospinal fluid. A combination of aggressive immunotherapy consisting of intravenous immunoglobulins, plasma exchange, rituximab and bortezomib resulted in clinical improvement with ambulation and non‐detectable anti‐neurofascin‐antibodies within the following 3 months. The follow‐up nerve conduction studies showed normalized amplitudes of the peripheral nerves with signs of reinnervation in electromyography. We conclude that an early aggressive immunotherapy consisting of a combination of rituximab and bortezomib could be considered as a therapeutic option for anti‐pan‐NF‐associated neuropathies.
    Type of Medium: Online Resource
    ISSN: 1085-9489 , 1529-8027
    URL: Issue
    URL: Article
    DOI: 10.1111/jns.v26.4
    DOI: 10.1111/jns.12465
    Language: English
    Publisher: Wiley
    Publication Date: 2021
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  • 9
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    Evaluation of the EFNS/PNS diagnostic criteria in a cohort of CIDP patients
    Wiley ; 2021
    In:  Annals of Clinical and Translational Neurology Vol. 8, No. 5 ( 2021-05), p. 1110-1121
    Details
    In: Annals of Clinical and Translational Neurology, Wiley, Vol. 8, No. 5 ( 2021-05), p. 1110-1121
    Abstract: To evaluate the European Federation of Neurological Societies (EFNS)/Peripheral Nerve Society (PNS) diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP) in a cohort of patients diagnosed and treated for CIDP in a tertiary university hospital. Methods In a monocentric retrospective study of 203 CIDP patients, diagnosed according to expert opinion, we evaluated the EFNS/PNS diagnostic criteria. Clinical course and nerve conduction studies (NCS) over 1 year from first referral were studied. Secondarily, we compared the clinical and paraclinical characteristics, including nerve ultrasound, of patients who failed with those who fulfilled the criteria in order to identify clinically relevant differences. Results At 1 year, 182 (89.7%) patients fulfilled the criteria (156/76.9% definite, 22/10.8% probable, and 4/2% possible). Twenty‐one (10.3%) patients did not because the electrodiagnostic criteria remained negative. These still showed signs of demyelination but did not reach the cut‐off values. They also presented typical, albeit less pronounced, multifocal nerve enlargement in ultrasonography. Mean disability at presentation and 1 year after was significantly lower. Most importantly, a relevant proportion of these patients also responded to therapy (6/21 = 28.6% vs. 82/182 = 45.3% of those fulfilling the criteria). Interpretation CIDP diagnosis could be established for 89.7% of patients over the course of 1 year using EFNS/PNS criteria. The remaining patients (10.3%) presented with milder disability, less accentuated demyelination, but otherwise similar characteristics and still considerable probability of treatment response. Failure to fulfill diagnostic criteria should not automatically preclude treatment. Nerve ultrasound should be considered as a complementary diagnostic tool to detect signs of inflammation in CIDP.
    Type of Medium: Online Resource
    ISSN: 2328-9503 , 2328-9503
    URL: Issue
    URL: Article
    DOI: 10.1002/acn3.v8.5
    DOI: 10.1002/acn3.51357
    Language: English
    Publisher: Wiley
    Publication Date: 2021
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  • 10
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    Immunomodulatory effects of oral dimethyl fumarate on intestinal immune regulation during experimental autoimmune neuritis in Lewis rats (P2.357)
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Neurology Vol. 88, No. 16_supplement ( 2017-04-18)
    Details
    In: Neurology, Ovid Technologies (Wolters Kluwer Health), Vol. 88, No. 16_supplement ( 2017-04-18)
    Type of Medium: Online Resource
    ISSN: 0028-3878 , 1526-632X
    URL: Article
    DOI: 10.1212/WNL.88.16_supplement.P2.357
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
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