Apheresis in Neurological Disorders

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Clinical Neurology".

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 43549

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Guest Editor
University of Ulm, Department of Neurology, RKU, Oberer Eselsberg 45, 89081 Ulm, Germany
Interests: apheresis; therapeutic plasma exchange; immunoadsorption; autoimmune diseases; multiple sclerosis; chronic inflammatory demyelinating polyneuropathy
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Special Issue Information

Dear Colleagues,

Apheresis refers to an extracorporeal therapy which aims at removing pathological constituents from the patients’ blood. Due to the development of new techniques as well as the discovery of novel autoimmune antibodies, it is increasingly recognized as an important therapeutic option for a variety of autoimmune-mediated neurological disorders, including multiple sclerosis, myasthenia gravis, autoimmune encephalitis, Guillain–Barré syndrome, and many others. Therapeutic plasma exchange (TPE) constitutes the standard method of apheresis for most indications, while immunoadsorption (IA) offers a more specific, low-risk alternative. Both methods aim at removing auto-antibodies from the blood. Evidence for most neurological diseases is still low. Interestingly, more recent developments suggest that apheresis is not limited to the removal of autoantibodies but may also be useful in neurodegenerative and possibly even in acute vascular disorders.

This Special Issue on apheresis in neurological disorders aims at:

(1) summarizing the current state of the art for the use of apheresis in neurological disorders;
(2) presenting up-to-date clinical studies which strengthen the evidence for or against the use of apheresis in various neurological disorders; and
(3) identifying novel targets and concepts for the use of apheresis in neurological disorders.

Authors are invited to contribute either original research articles or review articles to this Special Issue.

Dr. Johannes Dorst
Guest Editor

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Keywords

  • apheresis
  • therapeutic plasma exchange
  • immunoadsorption
  • autoimmune neurological diseases/disorders
  • multiple sclerosis
  • Guillain–Barré syndrome
  • chronic inflammatory demyelinating polyneuropathy
  • autoimmune encephalitis
  • myasthenia gravis

Published Papers (10 papers)

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Editorial

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5 pages, 185 KiB  
Editorial
Apheresis in Neurological Disorders
by Johannes Dorst
J. Clin. Med. 2020, 9(10), 3211; https://doi.org/10.3390/jcm9103211 - 06 Oct 2020
Cited by 1 | Viewed by 1818
Abstract
Plasma exchange (PE) and immunoadsorption (IA) constitute important options in the treatment of various autoimmune disorders across different medical disciplines [...] Full article
(This article belongs to the Special Issue Apheresis in Neurological Disorders)

Research

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12 pages, 245 KiB  
Article
Safety and Tolerability of Plasma Exchange and Immunoadsorption in Neuroinflammatory Diseases
by Johannes Dorst, Frank Fillies, Jens Dreyhaupt, Makbule Senel and Hayrettin Tumani
J. Clin. Med. 2020, 9(9), 2874; https://doi.org/10.3390/jcm9092874 - 05 Sep 2020
Cited by 12 | Viewed by 2722
Abstract
Plasma exchange (PE) and immunoadsorption (IA) are frequently used for treatment of various autoimmune-mediated neurological diseases, including multiple sclerosis (MS), chronic inflammatory demyelinating polyneuropathy (CIDP), and Guillain–Barré syndrome (GBS). Although both methods are generally regarded as well-tolerated treatment options, evidence for safety and [...] Read more.
Plasma exchange (PE) and immunoadsorption (IA) are frequently used for treatment of various autoimmune-mediated neurological diseases, including multiple sclerosis (MS), chronic inflammatory demyelinating polyneuropathy (CIDP), and Guillain–Barré syndrome (GBS). Although both methods are generally regarded as well-tolerated treatment options, evidence for safety and tolerability is low for most indications and largely relies on small case series. In this study, we retrospectively analysed adverse events (AEs) and laboratory changes in 284 patients with various neurological indications who received either PE (n = 65, 113 cycles) or IA (n = 219, 435 cycles) between 2013 and 2020 in our Neurology department. One standard treatment cycle for PE as well as IA consisted of five treatments on five consecutive days. During every treatment, the 2.0–2.5-fold individual plasma volume (PV) was treated in IA, while in PE, the 0.7-fold individual PV was replaced by human albumin solution. Overall, both methods showed an excellent safety profile; no deaths of life-threatening adverse events were recorded. Severe AEs (corresponding to grade 3 on the Common Terminology Criteria for Adverse Events grading scale v5.0) including three patients with sepsis, one pneumonia, and one pneumothorax were present in 5/435 IA cycles (1.1%); in the PE group, no severe AEs were recorded. Furthermore, although advantageous tolerability is generally considered the main advantage of IA over PE, we found that overall frequency of AEs (including grades 1 and 2) was higher in IA (67.1% of all cycles) compared to PE (35.4%; p < 0.001). The low incidence of AEs in PE might be caused by the lower PV exchanged during each treatment (0.7-fold) compared to previous studies which predominantly exchanged the 1.0–1.5-fold PV. In order to verify this hypothesis as well as confirming the efficacy of this lower-dosed scheme, prospective studies comparing different treatment regimens are needed. Full article
(This article belongs to the Special Issue Apheresis in Neurological Disorders)
13 pages, 4827 KiB  
Article
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Efficacy of Repeat Immunoadsorption
by Markus Tölle, Helma Freitag, Michaela Antelmann, Jelka Hartwig, Mirjam Schuchardt, Markus van der Giet, Kai-Uwe Eckardt, Patricia Grabowski and Carmen Scheibenbogen
J. Clin. Med. 2020, 9(8), 2443; https://doi.org/10.3390/jcm9082443 - 30 Jul 2020
Cited by 23 | Viewed by 10901
Abstract
(1) Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex neuroimmunological disease. There is evidence for an autoimmune mechanism for ME/CFS with an infection-triggered onset and dysfunction of ß2-adrenoreceptor antibodies (ß2AR-AB). In a first proof-of-concept study, we could show that [...] Read more.
(1) Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex neuroimmunological disease. There is evidence for an autoimmune mechanism for ME/CFS with an infection-triggered onset and dysfunction of ß2-adrenoreceptor antibodies (ß2AR-AB). In a first proof-of-concept study, we could show that IA was effective to reduce ß2AR-AB and led to improvement of various symptoms. (2) Five of the ME/CFS patients who had clinical improvement following treatment with a five-day IA were retreated in the current study about two years later with a modified IA protocol. The severity of symptoms was assessed by disease specific scores during a follow-up period of 12 months. The antibodies were determined by ELISA. (3) The modified IA treatment protocol resulted in a remarkable similar clinical response. The treatment was well tolerated and 80–90% decline of total IgG and ß2AR-AB was achieved. Four patients showed a rapid improvement in several clinical symptoms during IA therapy, lasting for six to 12 months. One patient had no improvement. (4) We could provide further evidence that IA has clinical efficacy in patients with ME/CFS. Data from our pilot trial warrant further controlled studies in ME/CFS. Full article
(This article belongs to the Special Issue Apheresis in Neurological Disorders)
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24 pages, 6024 KiB  
Article
Immunoadsorption and Plasma Exchange in Seropositive and Seronegative Immune-Mediated Neuropathies
by Alexander J. Davies, Janev Fehmi, Makbule Senel, Hayrettin Tumani, Johannes Dorst and Simon Rinaldi
J. Clin. Med. 2020, 9(7), 2025; https://doi.org/10.3390/jcm9072025 - 27 Jun 2020
Cited by 19 | Viewed by 3378
Abstract
The inflammatory neuropathies are disabling conditions with diverse immunological mechanisms. In some, a pathogenic role for immunoglobulin G (IgG)-class autoantibodies is increasingly appreciated, and immunoadsorption (IA) may therefore be a useful therapeutic option. We reviewed the use of and response to IA or [...] Read more.
The inflammatory neuropathies are disabling conditions with diverse immunological mechanisms. In some, a pathogenic role for immunoglobulin G (IgG)-class autoantibodies is increasingly appreciated, and immunoadsorption (IA) may therefore be a useful therapeutic option. We reviewed the use of and response to IA or plasma exchange (PLEx) in a cohort of 41 patients with nodal/paranodal antibodies identified from a total of 573 individuals with suspected inflammatory neuropathies during the course of routine diagnostic testing (PNAb cohort). 20 patients had been treated with PLEx and 4 with IA. Following a global but subjective evaluation by their treating clinicians, none of these patients were judged to have had a good response to either of these treatment modalities. Sequential serology of one PNAb+ case suggests prolonged suppression of antibody levels with frequent apheresis cycles or adjuvant therapies, may be required for effective treatment. We further retrospectively evaluated the serological status of 40 patients with either Guillain-Barré syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP), and a control group of 20 patients with clinically-isolated syndrome/multiple sclerosis (CIS/MS), who had all been treated with IgG-depleting IA (IA cohort). 32 of these patients (8/20 with CIDP, 13/20 with GBS, 11/20 with MS) were judged responsive to apheresis despite none of the serum samples from this cohort testing positive for IgG antibodies against glycolipids or nodal/paranodal cell-adhesion molecules. Although negative on antigen specific assays, three patients’ pre-treatment sera and eluates were reactive against different components of myelinating co-cultures. In summary, preliminary evidence suggests that GBS/CIDP patients without detectable IgG antibodies on routine diagnostic tests may nevertheless benefit from IA, and that an unbiased screening approach using myelinating co-cultures may assist in the detection of further autoantibodies which remain to be identified in such patients. Full article
(This article belongs to the Special Issue Apheresis in Neurological Disorders)
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23 pages, 1852 KiB  
Article
Immunoadsorption for Treatment of Patients with Suspected Alzheimer Dementia and Agonistic Autoantibodies against Alpha1a-Adrenoceptor—Rationale and Design of the IMAD Pilot Study
by Sylvia Stracke, Sandra Lange, Sarah Bornmann, Holger Kock, Lara Schulze, Johanna Klinger-König, Susanne Böhm, Antje Vogelgesang, Felix von Podewils, Agnes Föel, Stefan Gross, Katrin Wenzel, Gerd Wallukat, Harald Prüss, Alexander Dressel, Rudolf Kunze, Hans J. Grabe, Sönke Langner and Marcus Dörr
J. Clin. Med. 2020, 9(6), 1919; https://doi.org/10.3390/jcm9061919 - 19 Jun 2020
Cited by 4 | Viewed by 3577
Abstract
Background: agonistic autoantibodies (agAABs) against G protein-coupled receptors (GPCR) have been linked to cardiovascular disease. In dementia patients, GPCR-agAABs against the α1- and ß2-adrenoceptors (α1AR- and ß2AR) were found at a prevalence of 50%. Elimination of agAABs by immunoadsorption (IA) was successfully applied [...] Read more.
Background: agonistic autoantibodies (agAABs) against G protein-coupled receptors (GPCR) have been linked to cardiovascular disease. In dementia patients, GPCR-agAABs against the α1- and ß2-adrenoceptors (α1AR- and ß2AR) were found at a prevalence of 50%. Elimination of agAABs by immunoadsorption (IA) was successfully applied in cardiovascular disease. The IMAD trial (Efficacy of immunoadsorption for treatment of persons with Alzheimer dementia and agonistic autoantibodies against alpha1A-adrenoceptor) investigates whether the removal of α1AR-AABs by a 5-day IA procedure has a positive effect (improvement or non-deterioration) on changes of hemodynamic, cognitive, vascular and metabolic parameters in patients with suspected Alzheimer’s clinical syndrome within a one-year follow-up period. Methods: the IMAD trial is designed as an exploratory monocentric interventional trial corresponding to a proof-of-concept phase-IIa study. If cognition capacity of eligible patients scores 19–26 in the Mini Mental State Examination (MMSE), patients are tested for the presence of agAABs by an enzyme-linked immunosorbent assay (ELISA)-based method, followed by a bioassay-based confirmation test, further screening and treatment with IA and intravenous immunoglobulin G (IgG) replacement. We aim to include 15 patients with IA/IgG and to complete follow-up data from at least 12 patients. The primary outcome parameter of the study is uncorrected mean cerebral perfusion measured in mL/min/100 gr of brain tissue determined by magnetic resonance imaging with arterial spin labeling after 12 months. Conclusion: IMAD is an important pilot study that will analyze whether the removal of α1AR-agAABs by immunoadsorption in α1AR-agAAB-positive patients with suspected Alzheimer’s clinical syndrome may slow the progression of dementia and/or may improve vascular functional parameters. Full article
(This article belongs to the Special Issue Apheresis in Neurological Disorders)
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19 pages, 2586 KiB  
Article
Plasma Exchange or Immunoadsorption in Demyelinating Diseases: A Meta-Analysis
by Mark Lipphardt, Manuel Wallbach and Michael J. Koziolek
J. Clin. Med. 2020, 9(5), 1597; https://doi.org/10.3390/jcm9051597 - 25 May 2020
Cited by 22 | Viewed by 4393
Abstract
Multiple sclerosis (MS) is an inflammatory disease mainly affecting the central nervous system. In MS, abnormal immune mechanisms induce acute inflammation, demyelination, axonal loss, and the formation of central nervous system plaques. The long-term treatment involves options to modify the disease progression, whereas [...] Read more.
Multiple sclerosis (MS) is an inflammatory disease mainly affecting the central nervous system. In MS, abnormal immune mechanisms induce acute inflammation, demyelination, axonal loss, and the formation of central nervous system plaques. The long-term treatment involves options to modify the disease progression, whereas the treatment for the acute relapse has its focus in the administration of high-dose intravenous methylprednisolone (up to 1000 mg daily) over a period of three to five days as a first step. If symptoms of the acute relapse persist, it is defined as glucocorticosteroid-unresponsive, and immunomodulation by apheresis is recommended. However, several national and international guidelines have no uniform recommendations on using plasma exchange (PE) nor immunoadsorption (IA) in this case. A systematic review and meta-analysis was conducted, including observational studies or randomized controlled trials that investigated the effect of PE or IA on different courses of MS and neuromyelitis optica (NMO). One thousand, three hundred and eighty-three patients were included in the evaluation. Therapy response in relapsing-remitting MS and clinically isolated syndrome was 76.6% (95%CI 63.7–89.8%) in PE- and 80.6% (95%CI 69.3–91.8%) in IA-treated patients. Based on the recent literature, PE and IA may be considered as equal treatment possibilities in patients suffering from acute, glucocorticosteroid-unresponsive MS relapses. Full article
(This article belongs to the Special Issue Apheresis in Neurological Disorders)
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11 pages, 679 KiB  
Article
Comparing Plasma Exchange to Escalated Methyl Prednisolone in Refractory Multiple Sclerosis Relapses
by Steffen Pfeuffer, Leoni Rolfes, Eike Bormann, Cristina Sauerland, Tobias Ruck, Matthias Schilling, Nico Melzer, Marcus Brand, Refik Pul, Christoph Kleinschnitz, Heinz Wiendl and Sven G. Meuth
J. Clin. Med. 2020, 9(1), 35; https://doi.org/10.3390/jcm9010035 - 22 Dec 2019
Cited by 9 | Viewed by 2966
Abstract
Intravenous methyl prednisolone (IVMPS) represents the standard of care for multiple sclerosis (MS) relapses, but fail to improve symptoms in one quarter of patients. In this regard, apart from extending steroid treatment to a higher dose, therapeutic plasma exchange (TPE) has been recognized [...] Read more.
Intravenous methyl prednisolone (IVMPS) represents the standard of care for multiple sclerosis (MS) relapses, but fail to improve symptoms in one quarter of patients. In this regard, apart from extending steroid treatment to a higher dose, therapeutic plasma exchange (TPE) has been recognized as a treatment option. The aim of this retrospective, monocentric study was to investigate the efficacy of TPE versus escalated dosages of IVMPS in refractory MS relapses. An in-depth medical chart review was performed to identify patients from local databases. Relapse recovery was stratified as “good/full”, “average” and “worst/no” according to function score development. In total, 145 patients were analyzed. Good/average/worst recovery at discharge was observed in 60.9%/32.6%/6.5% of TPE versus 15.2%/14.1%/70.7% of IVMPS patients, respectively. A total of 53.5% of IVMPS patients received TPE as rescue treatment and 54.8% then responded satisfactorily. The multivariable odds ratio (OR) for worst/no recovery was 39.01 (95%–CI: 10.41–146.18; p ≤ 0.001), favoring administration of TPE as first escalation treatment. The effects were sustained at three-month follow-ups, as OR for further deterioration was 6.48 (95%–CI: 2.48–16.89; p ≤ 0.001), favoring TPE. In conclusion, TPE was superior over IVMPS in the amelioration of relapse symptoms at discharge and follow-up. This study provides class IV evidence supporting the administration of TPE as the first escalation treatment to steroid-refractory MS relapses. Full article
(This article belongs to the Special Issue Apheresis in Neurological Disorders)
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Review

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14 pages, 1569 KiB  
Review
Selective Apheresis of C-Reactive Protein for Treatment of Indications with Elevated CRP Concentrations
by Stefan Kayser, Patrizia Brunner, Katharina Althaus, Johannes Dorst and Ahmed Sheriff
J. Clin. Med. 2020, 9(9), 2947; https://doi.org/10.3390/jcm9092947 - 12 Sep 2020
Cited by 14 | Viewed by 5443
Abstract
Almost every kind of inflammation in the human body is accompanied by rising C-reactive protein (CRP) concentrations. This can include bacterial and viral infection, chronic inflammation and so-called sterile inflammation triggered by (internal) acute tissue injury. CRP is part of the ancient humoral [...] Read more.
Almost every kind of inflammation in the human body is accompanied by rising C-reactive protein (CRP) concentrations. This can include bacterial and viral infection, chronic inflammation and so-called sterile inflammation triggered by (internal) acute tissue injury. CRP is part of the ancient humoral immune response and secreted into the circulation by the liver upon respective stimuli. Its main immunological functions are the opsonization of biological particles (bacteria and dead or dying cells) for their clearance by macrophages and the activation of the classical complement pathway. This not only helps to eliminate pathogens and dead cells, which is very useful in any case, but unfortunately also to remove only slightly damaged or inactive human cells that may potentially regenerate with more CRP-free time. CRP action severely aggravates the extent of tissue damage during the acute phase response after an acute injury and therefore negatively affects clinical outcome. CRP is therefore a promising therapeutic target to rescue energy-deprived tissue either caused by ischemic injury (e.g., myocardial infarction and stroke) or by an overcompensating immune reaction occurring in acute inflammation (e.g., pancreatitis) or systemic inflammatory response syndrome (SIRS; e.g., after transplantation or surgery). Selective CRP apheresis can remove circulating CRP safely and efficiently. We explain the pathophysiological reasoning behind therapeutic CRP apheresis and summarize the broad span of indications in which its application could be beneficial with a focus on ischemic stroke as well as the results of this therapeutic approach after myocardial infarction. Full article
(This article belongs to the Special Issue Apheresis in Neurological Disorders)
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15 pages, 1787 KiB  
Review
Apheresis in Autoimmune Encephalitis and Autoimmune Dementia
by Rosa Rössling and Harald Prüss
J. Clin. Med. 2020, 9(9), 2683; https://doi.org/10.3390/jcm9092683 - 19 Aug 2020
Cited by 14 | Viewed by 3521
Abstract
Autoimmune encephalitis (AE) is a rapidly progressive inflammatory neurological disease. Underlying autoantibodies can bind to neuronal surfaces and synaptic proteins resulting in psychiatric symptoms, focal neurological signs, autonomic dysfunction and cognitive decline. Early and effective treatment is mandatory to reduce clinical symptoms and [...] Read more.
Autoimmune encephalitis (AE) is a rapidly progressive inflammatory neurological disease. Underlying autoantibodies can bind to neuronal surfaces and synaptic proteins resulting in psychiatric symptoms, focal neurological signs, autonomic dysfunction and cognitive decline. Early and effective treatment is mandatory to reduce clinical symptoms and to achieve remission. Therapeutic apheresis, involving both plasma exchange (PE) and immunoadsorption (IA), can rapidly remove pathogenic antibodies from the circulation, thus representing an important first-line treatment in AE patients. We here review the most relevant studies regarding therapeutic apheresis in AE, summarizing the outcome for patients and the expanding clinical spectrum of treatment-responsive clinical conditions. For example, patients with slowly progressing cognitive impairment suggesting a neurodegenerative dementia can have underlying autoantibodies and improve with therapeutic apheresis. Findings are encouraging and have led to the first ongoing clinical studies assessing the therapeutic effect of IA in patients with anti-neuronal autoantibodies and the clinical presentation of dementia. Therapeutic apheresis is an established and well tolerated option for first-line therapy in AE and, potentially, other antibody-mediated central nervous system diseases. Full article
(This article belongs to the Special Issue Apheresis in Neurological Disorders)
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22 pages, 885 KiB  
Review
Therapeutic Apheresis in Acute Relapsing Multiple Sclerosis: Current Evidence and Unmet Needs—A Systematic Review
by Leoni Rolfes, Steffen Pfeuffer, Tobias Ruck, Nico Melzer, Marc Pawlitzki, Michael Heming, Marcus Brand, Heinz Wiendl and Sven G. Meuth
J. Clin. Med. 2019, 8(10), 1623; https://doi.org/10.3390/jcm8101623 - 04 Oct 2019
Cited by 18 | Viewed by 3318
Abstract
Multiple sclerosis (MS) is the most abundant inflammatory demyelinating disorder of the central nervous system. Despite recent advances in its long-term immunomodulatory treatment, MS patients still suffer from relapses, significantly contributing to disability accrual. In recent years, apheresis procedures such as therapeutic plasma [...] Read more.
Multiple sclerosis (MS) is the most abundant inflammatory demyelinating disorder of the central nervous system. Despite recent advances in its long-term immunomodulatory treatment, MS patients still suffer from relapses, significantly contributing to disability accrual. In recent years, apheresis procedures such as therapeutic plasma exchange (TPE) and immunoadsorption (IA) have been recognized as two options for treating MS relapses, that do not respond to standard treatment with corticosteroids. TPE is already incorporated in most international guidelines, although evidence for its use resulted mostly from either case series or small unblinded and/or non-randomized trials. Data on IA are still sparse, but several studies indicate comparable efficacy between both apheresis procedures. This article gives an overview of the published evidence on TPE and IA in the treatment of acute relapses in MS. Further, we outline current evidence regarding individual outcome predictors, describe technical details of apheresis procedures, and discuss apheresis treatment in children and during pregnancy. Full article
(This article belongs to the Special Issue Apheresis in Neurological Disorders)
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