Background: Therapeutic plasma exchange (TPE) is a well-known apheresis technology since many years and is available worldwide. Myasthenia gravis is one of the first neurological diseases successfully treated with TPE. TPE is also frequently applied in acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barré syndrome). Both neurological disorders are immunologically mediated and might cause life-threatening symptoms in patients. Summary: There is a large body of evidence from many randomized controlled trials (RCTs) that the application of TPE in myasthenia gravis crisis or in acute Guillain-Barré syndrome is effective and safe. Thus, TPE is recommended as first-line therapy with a grade 1A recommendation during the critical course of these neurological diseases. Even chronic inflammatory demyelinating polyneuropathies characterized by complement-fixing autoantibodies to myelin are successfully treated with TPE. The plasma exchange reduces inflammatory cytokines, complements activating antibodies, and leads to an improvement of neurological symptoms. TPE is no standalone treatment but often combined with immunosuppressive therapy. Recent studies (clinical trials, retrospective analysis, meta-analysis, and systematic reviews) evaluate special apheresis technology (i.e., immunoadsorption [IA], small volume plasma exchange), compare different treatments of these neuropathies, or report on the therapy of rare immune-mediated neuropathies in case reports. Key Messages: TA is a well-established treatment and is safe in acute progressive neuropathies (myasthenia gravis, Guillain-Barré syndrome) with an immune etiology. TPE has been applied for decades and thus has the best evidence so far. The indication for IA depends on the availability of that technology and the evidence by RCTs in special neurological diseases. The treatment with TA should improve the clinical outcome of patients, reducing acute or chronic (chronic inflammatory demyelinating polyneuropathies) neurological symptoms. The informed consent of the patient should carefully weight risks and benefits of the apheresis treatment and consider alternative therapies.

According to the recommendations of the German Association of Blood Transfusion, treatment of neurologic patients with TA needs a therapeutic apheresis unit, a trained and experienced staff with specialized knowledge about the indications of TA, weighing potential risks and benefits for each patient [1]. Physicians specialized in transfusion medicine should plan the apheresis procedure together with the neurological clinic, developing a protocol (treatment plan) regarding the informed consent of patients, the concurrent therapy, vascular access, special monitoring (i.e., intensive care unit), anticoagulant therapy, and fluid replacement. Every single patient has to be carefully evaluated considering the patients’ disease state, the clinical conditions, and the current medication. Before starting the apheresis procedure, blood cell count, electrolytes (K, Na, Ca), and the blood coagulation screening (PT, aPTT) should be analyzed. Based on the pathogenesis of the disease, medical decision-making of TA depends on the potential benefit compared to the risks of the treatment, as well as treatment costs. Thus, the informed consent of the patient should also regard the alternatives of apheresis treatment and possible interactions of TA with other therapies.

The planning of TA needs exact recording of patient data. The body weight is used for the calculation of the total body volume (TBV), corrected by Gilcher’s rule or Nadler’s formula [2]. TBV and total plasma volume (TPV) are required to calculate the volume of plasma to be replaced in therapeutic plasma exchange (TPE) and to plan the number of apheresis procedures required for successful treatment. If extracorporeal blood volume exceeds 15% or intraprocedural hematocrit may fall below 24%, priming the apheresis set with RBC helps prevent hypovolemia.

Adequate blood flow is necessary for successful apheresis procedures. The optimum blood flow rate depends on the age, the TBV, the tolerance of the anticoagulant citrate, and the general clinical condition of the patient. Usually, peripheral veins are used for the vascular access. By use of central venous catheter (CVC), bearing the risks of vessel damage, hemorrhage, thrombosis, or infection, an informed consent about that procedure is required. In case of peripheral or central neuropathies in neurological diseases, limitations of the muscle contraction or the vascular tone may exist reducing blood flow prior to punctation or during apheresis. In case of reduced blood flow, the patient should be provided with a double lumen CVC suited for apheresis procedures which allows sufficient blood flow during TA required for successful treatment.

TPE started in 1959 as manual plasmapheresis in patients with macroglobulinemia, and it reduced serum viscosity successfully. Buckner et al. reported on the first automated plasma exchange performed with a new apheresis device (continuous flow centrifuge, NCI-IBM Blood Cell Separator) [3]. Nowadays, modern apheresis devices are on the market, which are validated for TPE by comparing continuous or intermittent flow separators in clinical trials [4]. In Neurology, disorders with an antibody based immune etiology, for instance myasthenia gravis (MG) or Guillain-Barré syndrome (GBS), have been accounted for the most prevalent indications of TPE in acute progressive neuropathies starting in the mid-eighties [5].

Autoimmunity may cause acquired neuropathy, associated with either acute or chronic antibody-mediated demyelination or disease-associated inflammation. TPE is applied to patients with a wide range of medical conditions and recommended, if clinical improvement might be expected from the reduction of disease-causing proteins or toxic substances. The ASFA guidelines give an excellent update every 3 years based on clinical studies about neurologic disorders successfully treated with TA. Treatment recommendations according to category I belong to disorders for which apheresis is accepted as first-line therapy, either as a primary standalone treatment or in conjunction with other modes of treatment [6]. An overview about the neurological diseases addressed in the recent version of the ASFA guidelines is presented in Table 1.

Table 1.

TA in neurological disease (adapted from ASFA Guidelines, 2019) [6]

 TA in neurological disease (adapted from ASFA Guidelines, 2019) [6]
 TA in neurological disease (adapted from ASFA Guidelines, 2019) [6]

Besides the ASFA guidelines, which are mainly used for TA procedures in the USA, other guidelines for TA exist in Europe, the UK, and Japan. In December 2021, the Japanese Society for Apheresis published their own Apheresis guidelines because of different principles of separation methods used in the USA and Europe (centrifugal separation) compared to Japan (membrane separation). Due to technical differences, development, background, as well as target diseases, the practice of TA in Japan differs from that in the USA, UK, and Europe and is difficult to adapt to the ASFA guidelines [7].

The treatment should improve the clinical outcome of the patient reducing acute or chronic neurologic symptoms. The therapeutic plan is discussed between the apheresis team and the neurology team. The applied treatment schedules are individually performed and depend on clinical indications, accompanied therapies, and relevant laboratory findings of the disease. The replacement fluids in TPE are mainly albumin and saline [8]. The processed volumes during apheresis range from 1.0 to 1.5 plasma volumes per apheresis session which shows the best efficacy (e.g., reduction of autoantibodies).

Immunoadsorption (IA) is defined as “binding of an antigen by a specific antibody that is attached to a surface, thus mediating removal of an antigen from a mixture” [9]. Compared to the TPE which reduces a majority of relevant plasma components, for instance immunoglobulins and coagulation factors only substituted by the replacement fluid albumin, IA removes selectively harmful substances of interest and nonspecific immunoglobulins from plasma depending on the applied IA technology.

The membrane technology mainly used in Japan depends on the fiber properties, the filter configuration and the typo membrane (material, pore size), allowing the passage of plasma constituents while retaining blood cells. The technical equipment of membrane separation differs from centrifuge separation or IA due to the device management, controlling the parameters for membrane plasma separation (e.g., transmembrane pressure) in addition to extracorporeal blood circulation, and the technology of the apheresis set. The technical characteristics of membrane devices for plasma separation are small size, transportable equipment, and no need for rotating centrifuge chambers equipped with rotating seals. The pore size, however, allows large plasma proteins, fibrinogen, and even immunoglobulins or immune complexes to pass the filter, while the cellular fractions (red blood cells, leukocytes, platelets) are drawn at the surface of the membrane. Depending on the hematocrit and the blood flow rate or blood shear rate, membrane pores might be blocked by red blood cells, and hemolysis may occur. Thus, the membrane technology requires control of the transmembrane pressure and the plasma removal should be limited to avoid high hematocrit during the passage of blood through the filter.

Autoimmune neurological disorders such as MG and GBS have been treated with different TA methods. By use of nonspecific IA with Staphylococcal protein A columns (PAA), the treated plasma is combined with the cellular components and returned to the patient. The PAA procedures last for two to 5 h treating 2.5 plasma volumes which results in a more than 90% reduction of immunoglobulin IgG1 and IgG2. Thus, substitution of IgG has to be considered in the treatment plan of the patient [10].

Several neurological diseases in childhood, notably movement disorders (e.g., Sydenham’s Chorea) or pediatric autoimmune neuropsychiatric disorders (e.g., PANDAS) associated with infections, may benefit from TPE (Table 1). TA in pediatric patients is challenging due to patients’ age and care, technical aspects (blood flow rate, blood counts, and blood volume), special venous catheters (CVC), and monitoring of the patients.

The following neurologic disorders are considered first-line therapy for TA, either treated with TPE or IA. This review summarizes relevant information from guidelines, meta-analysis, and randomized controlled studies and finally describes therapeutic principles which may be of practical interest for the planning of TA in neurological diseases.

MG, one of the first neurological diseases successfully treated with TPE, is a rare autoimmune disease characterized by a disturbance of the postsynaptic neuromuscular junction. Key neuromuscular junction protein directed autoantibodies which disrupt the neuromuscular transmission cause grave weakness typically found in MG. 85% of patients with MG have anti-acetylcholine-receptor antibodies which deplete the ACh-receptor (ACh-R) function. In 10% of patients with severe MG, antibodies against muscle-specific kinase (MuSK) are found.

According to the ASFA guidelines, acute short-term treatment with either TPE or IA is recommended (grade 1B, category I). Long-term treatment is a low-grade recommendation (grade 2B, category II), limited for instance to the application of TA in therapy refractory patients, whereas immunosuppressive drugs (corticosteroids and azathioprine) are the first-line therapy.

According to the international consensus guidance for the management of MG prepared by the Task Force of the MG Foundation of America, guidance statements were developed. TPE and intravenous immunoglobulin (IVIG) are appropriately used as short-term treatments in patients with life-threatening signs of MG (respiratory insufficiency or dysphagia), in patients with refractory MG or in preparation for surgery of bulbar dysfunction. TPE and IVIG are alternative treatments in MG and probably equally effective in severe or generalized MG. TPE may be more effective in MuSK-MG. In case of myasthenic crisis, the expert consensus suggests that TPE works more quickly compared to IVIG. While TPE should not be used in sepsis, IVIG may be of disadvantage in hypercoagulability, renal failure, or hypersensitivity to immunoglobulin [11].

Depending on availability, TPE or IA might be used with comparable therapeutic efficiency. In two third of patients with acute MG, TPE processed with less than one TBV lower clinical symptoms of MG. Concomitant immunosuppressive therapy has to be initiated to reduce autoimmune activity. Besides first- and second-line immunosuppression, emerging drugs such as rituximab and the complement inhibitor eculizumab are under evaluation for the application in MG [12]. Immunomodulation with immunoglobulins (IVIG) is frequently used as alternative to TPE which has been subject to several comparative studies.

Prospective studies, meta-analysis, and recommendations:

Between 1966 and 2002, TPE for generalized MG was only investigated in one prospective controlled trial and compared with corticosteroid treatment (MEDLINE search), which did not show a significant difference of clinical endpoints (muscle score, relapses, and mean (SD) prednisone dose) [13]. Many non-randomized studies showed a benefit of patients treated with TPE. The Cochrane Database review also revealed that many case series exist which describe a short-term benefit from TPE. Only one of four randomized controlled trials (RCTs) with 35 participants showed a significant difference (weak statistical power) in favor of TPE before thymectomy, whereas other RCTs did not find a difference between TPE and corticosteroids or IVIG [13, 14]. Another RCT presented results of 19 patients with MG crisis. 10 patients received TPE and 9 patients received IA, both combined with drug treatment. Patients from both treatment groups improved to a stable clinical status after three to five treatment sessions [15].

Evaluation of the efficacy and safety over a short period of IVIG versus TPE was performed by a review of 10 articles about MG (Cochrane Neuromuscular Disease Group trails). It reveals no evidence of a difference due to efficacy and safety [16]. A retrospective study analyzed standard TPE with IA alone or in alternating combination. IA in combination with TPE or IA alone was associated with a shorter hospital stay and reduction of MG score compared to TPE. Allergic reactions or hypocoagulability were significantly more frequent in the TPE group [17]. One of the first clinical studies about the clearance of plasma of MG patients by IA was published in 1995, presenting the clinical results of 16 patients with moderately severe to severe generalized MG by IA (4 days treatment, 4 IA treatments). It found normalized ACh-R antibody levels after one to 3 weeks as well as clinical improvement in 14 patients. Compared to TPE the protein loss by IA was lower [18].

An open-label trial about the longitudinal results of TPE in 10 patients evaluated validated disease-specific measures (i.e., MG score, manual muscle test, daily living profile, quality of life). TPE resulted in rapid improvement of these clinical scores for MG [19]. The use of a new IA technology with tryptophan-immobilized column (SelA) was validated in four patients applying 14 apheresis sessions with conventional apheresis devices. By use of SelA column compared with 5 IA procedures in an observational study, removal of Ach-R antibodies, fibrinogen, and factor XIII was higher with IA treatment. Tryptophan-immobilized column retained fibrinogen and factor XIII. Thus, autoantibody removal by IA might be combined with SelA to reduce loss of coagulation factors [20]. Recently, a prospective RCT about the effects of TPE combined with IVIG in sixty patients with MG crisis describes that consciousness, immune function, and prognosis of these patients enhanced and the treatment is safe [21].

GBS, in 90% acute inflammatory demyelinating polyradiculoneuropathy, is immunologically mediated. This radiculoneuropathy of spinal nerve roots and peripheral nerves is caused by an acute-onset inflammatory disease triggered by infection, cellular immune disturbance, or autoimmunity. The clinical course of that rare disease (1/100.000) is characterized by weakness, starting in the distal limps and affecting proximal muscle function, known as symmetrically “ascending paralysis,” which might cause respiratory paralysis. GBS shows an acute onset of disease, mostly after infections (“influenza-like illness”) during the recovery period, starting with weakness and a neuropathy of the motor and sensory peripheral nerves. Immunologic reactions either by T cells or by antibodies cross-reacting with peripheral nerve antigens are relevant for that radiculoneuropathy. Cerebrospinal fluids typically show signs of inflammation with elevated protein levels. Reduced nerve conduction velocities and areflexia are related to the multifocal destruction of myelin segments and axons. In severe cases, oropharyngeal muscles might be affected, which requires mechanical ventilation. 20% patients are long-term affected by neurologic symptoms (mortality rate up to 5%). Ganglioside autoantibodies, such as GM1, GD1a, and GM1b might be of diagnostic relevance in special axonal forms of GBS. In most of the patients, spontaneous recovery from neurologic symptoms appears. Subtypes and other variants consist of special symptoms. The Miller Fisher syndrome is characterized by ophthalmoplegia, ataxia, and areflexia [22].

The ASFA guidelines recommend TPE as primary treatment mainly in severe GBS (paralytic phase) supporting ICU therapy, mechanical ventilation therapy, disability, as well as recovery time. The North American Guillain-Barré Study Group trial reported in 1985 that the mechanical ventilation therapy was shorten by half applying TPE [23]. TPE is a treatment of Category I with a recommendation grade 1A. The recommendation grade 1B of IA describes a strong recommendation for IA with moderate-quality evidence due to lower evidence by clinical studies so far. Most of the RCTs were performed with TPE, the first TA, which improved the neurologic symptoms of severe GBS and confirmed therapeutic efficacy. As IVIG therapy (0.4 g/kg body weight) is also effective in GBS, comparative studies between both treatments and combined application of TPE and IVIG in GBS have been performed. Usually, TPE with a frequency of five plasma volumes over 10 days was performed, or IVIG within 2 weeks of onset with 2 g/kg body weight over 2 days. The largest international multicenter RCT compared TPE, IVIG, and TPE followed by IVIG therapy in GBS patients (severe acute inflammatory demyelinating polyradiculoneuropathy, n = 383) and found all therapeutic modalities, TPE (49 days), IVIG (51 days), and combined therapy (40 days) to be equivalent due to disability, improvement at 4 weeks, and time to be able to walk without assistance (Guillain-Barre Syndrome Trial Group, 1997) [24]. Since IVIG is readily available in terms of immunomodulatory treatment, it is mostly used to initiate therapy (0.4 g/kg, 5 days). There are several meta-analysis and systematic reviews of the Cochrane Database, analyzing the application of TPE or IVIG in GBS [25]. Chevret et al. reported on six trials concerning 649 participants comparing TPE with supportive treatment and showed moderate-quality evidence for more improvement with TPE compared with supportive care alone. Another Cochrane report on six RCTs (151 participants) found none of these trials large enough to evaluate the treatment with alternative drugs (i.e., interferon, eculizumab). Finally, TPE and IVIG may help improving the recovery from GBS, but patients with GBS may have long-term disability [26].

The use of IA avoids the need of replacing human plasma products and was used with similar efficacy as TPE [27]. Recently, Lin et al. reported on a network meta-analysis (NMA study) which included 2,474 patients from 28 trials (15 different therapies). The corticosteroids did not show improvement compared to placebo; TPE and IVIG were more effective than placebo, and there was no significant difference between doses and courses of TPE and IVIG. Other therapies or combination therapies, such as IVIG and eculizumab, or IA followed by TPE and IVIG did not show significant advantage [28]. The American Academy of Neurology recommended in 2011 that plasmapheresis is established as effective and should be offered in severe acute inflammatory demyelinating polyneuropathy/GBS and in the short-term management of chronic inflammatory demyelinating polyneuropathy (CIDP) (class I studies, level A) [29].

The ASFA guidelines describe the rationale for TPE as the autoimmune antibody-mediated damage to peripheral nerve myelin because clinical studies on additional treatment with TPE in acute inflammatory demyelinating polyneuropathy/GBS revealed an improved outcome to accelerate motor recovery in patients compared with the classical therapy alone. The Cochrane Neuromuscular Disease Group concluded on the basis of study reviews that TPE is effective and should be initiated within 7 days of disease onset [25]. The decision about the combination of TPE with IVIG has to be made in every single patient because of limited evidence based on studies. During TPE, the patients should be monitored carefully. Treatment duration last for 2–3 weeks until clinical relapse occur.

A retrospective evaluation (n = 23 patients, n = 186 TPE treatments) about the long-term efficacy, tolerability, and safety in children with various neuroimmunological disorders found TPE to be effective, especially in GBS and MG and well tolerated in children. Mostly, electrolyte disturbances were recorded as side effects of TPE [30]. The recommendation on childhood and adolescence with GBS is related to recommendations in adults. A systematic analysis of the literature revealed that only a few adequately controlled studies exist for this particular age group [31]. For adult patients with GBS, there are a higher number of suitable studies available. IVIG is recommended for severe or persistently progressive GBS treatment. TPE is recommended in cases of IVIG intolerance or inefficacy.

Current clinical trials address variable procedures for TPE or treatment regiments. Recently, a phase II safety and feasibility study (National Institute of Neurosciences and Hospital, Dhaka, Bangladesh, trial registration number NCT02780570) investigated small volume plasma exchange, a procedure with blood-cell sedimentation, removal of supernatant plasma, and retransfusion of blood cells, in 20 adult patients with GBS (replacement fluid fresh frozen plasma and normal saline). This alternative treatment to TPE with apheresis or IVIG seems to be safe and feasible but needs further studies to evaluate the clinical efficacy [32].

CIDP is a heterogeneous group of chronic inflammatory neuropathies. It is characterized by slowly progressive symmetric mixed sensorimotor polyneuropathy with proximal and distal muscle paresis in an intermittent or continuous course over 2 month. Nerve biopsy reveals demyelation and axonopathy often caused by inflammatory cell infiltrates due to a disturbance of the immune system. Several immune disorders have been found to initiate CIDP (i.e., monoclonal gammopathy, connective tissue disease, inflammatory bowel disease), but the pathogenesis of CIDP is heterogenous and only partly known so far. In rare cases, pregnancy may trigger CIDP which have a higher risk of relapse during pregnancy [33, 34].

The pathology of these inflammatory neuropathies is characterized by complement-fixing immunoglobulins (autoantibodies) often found on myelin sheaths which cause macrophage recruitment and myelin phagocytosis, responsible for segmental demyelination of axons and proliferation of Schwann cells. The peripheral nerve damage can be either progressive or relapsing and respond to immunosuppressive or immunomodulatory therapies. After failure of the first-line therapy with corticosteroids, other imunosuppressive therapies (azathioprine, cyclophosphamide, methotrexate, rituximab or alemtuzumab, cyclosporine, interferon-beta) may be useful. Although several autoantibodies were detected in CIDP, the utility as biomarkers has to be further evaluated. Variants of CIDP different from typical CIDP (frequency approx. 50%) show different clinical presentation including focal, multifocal motor, and sensory CIDP. CIDP variants with variability of clinical symptoms and different immunopathological findings or phenotypes may response diversely to treatments [35].

The pathogenesis of CIPD is mainly based on autoimmune disturbance of cellular and humoral immunity. Antibodies against gangliosides which are part of the glycolipid components, found on the surface of all eukaryotic plasma membranes, constitute 5–10% of the total lipid mass of the plasma membrane in nerve cells (more than 40 different gangliosides identified) and may be important because of their electrical effects, alternating the electrical field across the nerve cell membrane. TPE reduce the burden of inflammatory cytokines and complement activating antibodies of plasma which may cause the neurological damage to peripheral nerves [36]. Thus, control of biomarkers, for instance myelin-associated glycoprotein (MAG) in monoclonal gammopathies, and against other proteins (contactin-1, contactin-associated protein-1, neurofascin-155) may be of relevance and its utility for treatment control is still under evaluation [37].

The recommendations from ASFA guidelines describe three first-line treatments, corticosteroids, IVIG, and TPE. Corticosteroid treatment is mostly available; IVIG is effective but costly. Thus, in relapsing course of CIDP, TPE may provide an alternative treatment for patients. Herein, five to ten treatment session, every other day, applied within two to 4 weeks are commonly used, depending on the clinical improvement of the patient. 50–80% of the patients with CIDP have short-term improvement after TPE. Until 2019, the ASFA guidelines reported on 3 RCT about TPE and 2 RCT about IA for the treatment of CIDP. Finally, a 1B grade recommendation (category I) resulted for the use of TPE in CIDP. The following subtypes were included: multifocal motor neuropathy, Lewis-Sumner syndrome (multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), and distal acquired demyelinating neuropathy [6].

Evidence from clinical trials is in favor of IVIG or TPE and treatment decision depends on ease of administration, cost, availability, and side effects. The treatment intention is to stop the inflammatory process which is responsible for demyelination and axon damage. Therapeutic response is clinically controlled observing the stabilization or improvement of neurological symptoms of patients of this highly diverse group of neuropathies. Secondary therapies are used to reduce long-term steroid dose (side effects) or to replace successful TPE (availability, patient monitoring) and include immunosuppressive therapy, such as azathioprine, cyclophosphamide, methotrexate, rituximab, and interferon-beta.

During the last 25 years, several RCTs have been performed and revealed the volume per kilogram body weight of plasma exchange (40–50 mL/kg, 1–1.5 TBV), the frequency of TPE per week (2–3 TPE per week until improvement), and the duration of TPE (3–5 weeks) for CIDP patients. Application of TPE twice weekly for 3 weeks showed improvement of CIDP [38]. A randomized double-blind crossover trial in 1994 reported on TPE with a frequency of twice a week for 3 weeks, followed by once a week for 3 weeks, and compared it with IVIG 0.4 g/kg once a week for 3 weeks, followed by 0.2 g/kg once a week for 3 weeks. TPE (replacement fluid serum albumin) and IVIG resulted in significant improvement of the neurologic-disability score in five patients and in subset scores for weakness and reflex in 4 patients [39].

Comparison between TPE and IA was performed by a randomized pilot trial in nine patients which received each 6 treatments (plasma volume of 2.5 L per treatment) and resulted both in immediately clinical improvement with completion of the apheresis treatment sessions (44 vs. 67% of patients). IA is at least equally effective and safe in CIDP patients compared to TPE [40]. In a prospective study, short-term and long-term effects of IA in CIDP patients were compared, and it also found clinical improvement due to CIDP score (muscle strength). IA in regular intervals (long-term) might constitute a promising and well-tolerated alterative treatment stabilizing the course of CIDP [41]. In a retrospective study, IA was effective in 14 CIDP outpatient clinics using IA with 1–2 treatments per week. Maintenance IA resulted in an improvement of disability. IA was safe and well tolerated without side effects. In CIDP patients unresponsive to first-line treatment or for maintenance treatment avoiding regular replacement of human plasma products, IA is effective and safe [42]. Less than 25% CIDP patients do not respond to corticosteroids, IVIG or TPE. Failure to first-line treatment is an indication for immunosuppressive second-line therapy. 64% of patients respond to rituximab or cyclophosphamide [43].

According to the ASFA recommendation, TPE or IA provides short-term benefit, but rapid deterioration may occur afterward. This may necessitate maintenance treatment, with repeated TPE, IA, and/or other immunomodulating therapies, with frequency tailored to symptoms and tolerability of the individual patient [6]. The American Academy of Neurology (AAN) recommended in 2011 that plasmapheresis is established as effective and should be offered in severe acute inflammatory demyelinating polyneuropathy/GBS and in the short-term management of CIDP. However, this guideline is not updated since 2018 (guideline retired on Oct 2018). The Guideline Subcommittee which reviews AAN guidelines every 3 years for currency and retires those that are no longer up to date did not decide to create a new guideline on that topic so far [29]. The CIDP outcome study (ICOS) based on the treatment with IVIG, corticosteroids monotherapy, or combination treatment measuring clinical symptoms (i.e., Rasch-built overall disability scale, I-RODS and MRC sum score) revealed the treatment changes and residual symptoms at 1 year and found 36% of the treated patients in remission. In most patients (94%) started with IVIG, neurological symptoms improved. Remission was found in 44% of patients started with combined treatment [44].

A clinical neurological problem with polyneuropathy, mainly sensory symptoms, could be associated with monoclonal gammopathy, following an acute, subacute, or chronical course. This neurological problem is categorized as chronic acquired demyelinating polyneuropathy and associated with other demyelinating neuropathies. Notably B-cell tumors produce monoclonal immunoglobulins (IgM, IgG, IgA) or immunoglobulin fragments (paraproteins) that might damage nerves by deposition of paraproteins in myelin lamellae responsible for demyelinating neuropathies. Immunoglobulin light chain-derived amyloid may also cause neurotoxic effects and lead to peripheral neuropathy.

Anti-MAG neuropathy is associated with monoclonal gammopathy of different origin (MGUS, Waldenström macroglobulinemia, or B-cell lymphoma). The detection of the IgM monoclonal gammopathy-associated neuropathy (anti-MAG neuropathy), associated with ataxia and neurogenic tremor, and the motor neuropathy, depends on typical neurological symptoms and specific autoantibodies (anti-MAG).

The therapeutic rational of TA is unclear, so far. The main therapeutic principle is the specific treatment of the underlying disease. Cytotoxic therapy for immunosuppression (cyclophosphamide) may lead to transient improvement but is associated with toxicity and of limited value. Response to IVIG is seen during initial treatment within several days until weeks and is used to reduce the risk of disease progression.

A large meta-analysis reveals limited support for the use of TPE, cyclophosphamide combined with prednisolone, IVIG, and corticosteroids for IgG and IgA paraproteinemic neuropathies. Treatments such as plasma exchange, corticosteroids, or IVIG have been mainly examined in nonrandomized studies of patients with IgG and IgA paraproteinemic neuropathy. However, there is no sufficient evidence from RCTs for the treatment of IgG or IgA paraproteinemic neuropathy. The authors conclude that more RCTs of existing, and new treatments are required [45, 46].

In anti-MAG paraproteinemic neuropathy in support of any particular treatment, IVIG and rituximab are the most frequently used medications. Clinical improvement is often seen after a 50% reduction of serum IgM.

The rationale for the TA is to reduce antibodies, notably anti-MAG or pathogenetic antibodies or antibody fragments (paraproteins), responsible for neuropathy. Clinical improvement may be expected from significant reduction of these antibodies. The ASFA guidelines recommend a TPE of 1.0–1.5 TBV, albumin as replacement fluid and at least five to six treatments over 10–14 days by control of the improvement of neurologic symptoms [6].

1. The treatment with TA should improve the clinical outcome of patients reducing acute or chronic neurological symptoms.

2. The informed consent of the patient should carefully weight risk and benefit of the apheresis treatment considering alternative therapy.

3. Most prevalent indications of TPE (best evidence by RCTs) are acute progressive neuropathies with an antibody based immune etiology.

The principles of apheresis treatment are as follows:

1. In neurological disorders, reduced muscle contraction or vascular tone could reduce the blood flow and may favor the indication for CVC for the apheresis treatment.

2. The replacement fluids of TPE are albumin or saline. Electrolytes (e. g. calcium) have to be monitored and substituted. In intensive TPE protocols, depletion of plasma proteins may cause coagulation factor deficiency (e. g. fibrinogen). Monitoring of immunoglobulin IgG is required to recognize immunodeficiency and to consider the substitution of immunoglobulins in the treatment plan. Thus, replacement strategies have to be prepared and described in protocols prior to TA.

3. The processed blood volume of 1.0–1.5 plasma volumes showed the best efficiency of plasma exchange in TPE.

4. The starting frequency of TA is recommended with 3–5 treatment procedures per week for a period of 1–3 weeks.

5. The therapy control in neurological disorders during TA is mainly the improvement of acute or chronic neurological symptoms.

6. The treatments of TPE or IA (increasing evidence) alone or in combination with IVIG are appropriately used as short-term treatments in patients with life-threating symptoms in MG (i.e., MG crisis), in severe GBS, or in chronical neuropathies.

7. The frequency of TA depends on the improvement of the neurological symptoms of the patients (Table 1).

TA is a well-established treatment and safe in acute neuropathies with an immune etiology. TPE is applied for decades and thus has the best evidence so far. The indication for IA depends on the availability of that technology and the increasing evidence by RCTs.

The author has no conflict of interest to declare.

No funding was received for this study.

Erwin Strasser wrote the manuscript and approved its final content.

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