A randomized and controlled study comparing immunoadsorption and plasma exchange in myasthenic crisis

Myasthenic crisis is the most serious life-threatening event in Myasthenia gravis patients, affecting up to 27% within the first two years after onset of disease. Extracorporeal removal of circulating autoantibodies against the nicotinic acetylcholine receptor (AChRAb) by methods of therapeutic apheresis, e.g. plasma exchange (PE) and immunoadsorption (IA) had been demonstrated as effective treatment especially in acute situations of myasthenic crisis. However, controlled data comparing clinical safety and efficacy of both methods in a clinical study were not available. Here the results of a prospective randomized controlled clinical trial are presented, investigating 19 patients with myasthenic crisis, who were randomized to receive either PE (n = 10) or IA (n = 9) in addition to combined drug treatment. Patients received 3 to 5 (mean 3.5 for PE, and 3.4 for IA) treatments over a period of 7 days with a predefined treatment volume of 1.5 l plasma (i.e., 20-25 ml/kg plasma representing 0.5-0.6 patients' plasma volumes). Clinical courses were monitored using disease specific clinical scores. After initiation of IA or PE the mean value of Myasthenia scores decreased equally until Day 14 of the post-treatment phase. Patients from both treatment groups improved to a stable clinical status of Oosterhuis Classes 1 and 2. Substantial reduction of AChRAb was documented after each session of PE or IA. In the treatment period 16 adverse effects (seven serious adverse events, SAE) in the PE and 10 (1 SAE) in the IA group were observed. In conclusion, IA proved to be equally effective compared with PE treatment in patients with myasthenic crisis. Three to five treatment sessions using low plasma volume dosage of 20-25 ml/kg were adequate to improve clinically relevant symptoms significantly in most patients.     

A prominent elevation of glial fibrillary acidic protein in the cerebrospinal fluid during relapse in neuromyelitis optica

Neuromyelitis optica (NMO) is a neurologic disease characterized by severe optic neuritis, longitudinally extended, transverse myelitis and serum aquaporin-4 (AQP4) antibody. Our recent neuropathological study revealed the extensive loss of AQP4 and glial fibrillary acidic protein (GFAP), an astrocyte-specific protein, in NMO lesions, but not in MS lesions, suggesting that severe astrocytic damage or dysfunction may be related to the pathogenesis of NMO. Here we report a patient of NMO, in which the cerebrospinal fluid (CSF) levels of GFAP were measured both during relapse of myelitis and after high-dose intravenous methylprednisolone (HIMP). The patient was a 34-year old woman with two previous episodes of optic neuritis. She developed myelitis longitudinally extending from C3 to T12 with contrast enhancement, and was AQP4 antibody-positive. In the acute phase, the GFAP level in the cerebrospinal fluid (CSF) was prominently elevated (18,966.7 ng/ml) as compared with controls (0.6 +/- 0.33 ng/ml). However, following HIMP, the clinical and MRI findings improved, and the CSF-GFAP level was near-normal (2.1 ng/ml). The CSF of myelin basic protein was also elevated in relapse (1,016.0 pg/ml), and became lower but still remained high (158.7 pg/ml) after HIMP compared with controls (3.36 +/- 3.83 pg/ml). The prominent elevation of the CSF-GFAP level in relapse of NMO, followed by its sharp decline after therapy, suggests severe astrocytic damage with a temporal profile distinct from that of the demyelinating process in NMO. CSF-GFAP may be useful as a biomarker of NMO.     

Immunoadsorption in Guillain-Barré syndrome and myasthenia gravis.

Elimination of circulating antibodies by hemapheresis is an empirical treatment concept in various neuroimmunological diseases. Plasma exchange (PE) has been shown to be superior to symptomatic treatment in Guillain-Barré syndrome (GBS) in two large multicenter studies. It is also effective in myasthenia gravis (MG), although no comparative studies have been performed. Immunoadsorption (IA) using polyvinyl alcohol gel columns to which phenylalanin (IM-PH) or tryptophan (IM-TR) are covalently bound is an alternative to PE, and seems to have equal efficacy and comparable side effects. This method also obviates the need for replacement of plasma with human albumin or plasma. We compared the treatment results of 11 patients with GBS treated by PE to those of 13 patients treated by IA using an IM-TR column. Here, we found no statistically significant differences with regard to efficacy and clinical or procedural complications. From these data we conclude that immunoadsorption can be used as an equal alternative to PE. A large multicenter study comparing PE, intravenous immunoglobulins (IVIG), and the combination of both in the treatment of GBS revealed no significant difference between the 3 treatment groups. In MG, only 2 small studies have been performed using IA, and no studies comparing PE or other treatments to IA have been conducted. Both investigations of IA therapy demonstrated a marked reduction in the acetylcholine receptor (AchR) antibodies and a sustained improvement of the clinical signs. These results therefore show that IA is an effective treatment for myasthenia gravis.     

Long‐term plasma exchange for severe refractory hypertriglyceridemia: A decade of experience demonstrates safety and efficacy

Hypertriglyceridemia (hyperTG) is a common form of dyslipidemia and is frequently associated with premature coronary disease, and when severe, recurrent events of pancreatitis may occur. The management of hyperTG is generally medical (life style modification, medications). Plasma exchange (PE) has been reported to be useful in emergency situations particularly when acute pancreatitis results from extreme hyperTG. To our knowledge, there is only one report on long‐term use of PE for hyperTG. We here report our results of long‐term treatment of hyperTG in 6 patients with Frederickson Type V hyperlipidemia who had recurrent attacks of pancreatitis due to hyperTG refractory to medical therapy. PE was performed from one to eight times a month, mostly using a Cobe Spectra apparatus. In total, our center has performed a total of 1,593 PE sessions for hyperTG. There were no safety issues associated with PE for hyperTG other than occasional access problems (clotted fistula, IV access problems). Determination of plasma TG levels before and after PE demonstrated high efficiency of TG removal (42% to 58% reduction). There was marked clinical improvement in recurrent pancreatitis; patients had a major decrease in episodes (39% to 100%) while on regular PE, as long as they adhered to the treatment schedule. We conclude that long‐term PE for hyperTG, while costly, is feasible and safe and may reduce recurrent attacks of pancreatitis. J. Clin. Apheresis, 2009. © 2009 Wiley‐Liss, Inc.     

Plasma Exchange and Immunoadsorption of Patients with Thoracic Organ Transplantation

Primary organ failure after transplantation (TX) remains a serious complication and leads to a high percentage of lethality. It is known, however, that the speed of rejection and tissue destruction depends on 3 main factors: antibody titer, the ability of the tissue to repair itself, and immunosuppressive measures. Especially with evidence for antibodies against human leukocyte antigen (HLA-ab), the immunological risk of persistent and acute episodes of rejection increases. The role of non-HLA-ab in rejection episodes is often underestimated and should be studied further. Antibody-mediated rejection (AMR) is still an unsolved problem in thoracic organ TX. An essential pillar of antihumoral therapy are the extracorporeal procedures like plasmapheresis (PP), therapeutic plasma exchange (TPE), and immunoadsorption (IA), because only they have the ability to remove preformed or de novo developed antibodies quickly and effectively. The quick removal of antibodies and other plasma factors through TPE or IA remains an effective and supportive method for treating AMR and allows the TX despite preformed antibodies. The pertinent literature does not disclose, however, how often and for how long treatment should be administered. It is known, that repeated treatment cycles with adequately processed plasma volume must be used to overcome redistribution of pathological antibodies. Based on our experience in heart transplant recipients with compromised graft function due to non-HLA-ab and HLA-ab, IA seems to be more effective.     

血浆置换治疗视神经脊髓炎谱系疾病及其有效性分析——附4例报告

目的探讨血浆置换(PE)对激素治疗无效的视神经脊髓炎谱系疾病(NMOSD)的治疗效果。方法收集本院2016-2017年神经病学中心神经感染与免疫疾病科收治住院的84名NMOSD患者的病历资料,从中选择出因激素治疗无效而采用PE治疗的急性期NMOSD病例,采用回顾性分析方法比较治疗前后扩展残疾状态量表评分(EDSS)的差异,评价PE疗效和副作用,并与仅用大剂量甲泼尼龙冲击治疗NMOSD病例的显效时间、EDSS评分作对比。结果本组中因激素治疗无效而采用PE治疗的急性期NMOSD患者的比例为4.76%(4/84);PE置换量183-1625.4(中位数1118.7)mL/次;经PE治疗后EDSS评分由6.13±0.41降为4.88±0.96(P<0.05),EDSS平均下降1.25分;而经激素冲击治疗后EDSS平均下降0.75分。患者视力、肌力较前好转时间:采用PE者1-3(中位数2.5)d(1例于PE 1.5 h时出现过敏反应,PE治疗后EDSS下降2分);仅采用激素冲击治疗者2-14(中位数6.4)d。本组经PE治疗的NMOSD患者除抗-AQP4,其他免疫抗体,包括抗核抗体、抗-SSA、抗-SSB、RO-52抗体阳性效价明显下降。结论 PE对常规疗法无效的NMOSD具有较快缓解和稳定病情的作用,可能对难治性NMOSD是1种有效、安全的疗法。     

罕见视神经脊髓炎合并系统性红斑狼疮1例并文献复习

报告1例罕见病变累及8个脊髓节段的视神经脊髓炎合并系统性红斑狼疮的病例,分析其发病现状和最新进展,并复习相关文献。1名48岁女性,因"左眼视力下降2个月,双下肢麻痹无力伴胸痛3d"入院,眼底血管造影提示左眼球后视神经炎,脊髓MRI提示C_5~T_7脊髓炎,经综合治疗后病情好转。视神经脊髓炎合并系统性红斑狼疮发病非常罕见,其发病机制与广泛的自体免疫性疾病有关,及时正确诊断和治疗对患者的预后起至关重要的作用。     

ABO-incompatible allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning: Close association with transplant-associated microangiopathy.

Transplant-associated microangiopathy (TAM) is a severe complication following allogeneic hematopoietic stem cell transplantation (HSCT) even after reduced-intensity conditioning (RIC). Data on 112 patients following RIC were analyzed with respect to TAM according to the ASBMT and risk factors, response to well-defined therapy and outcome were determined. TAM occurred in 11 of 112 patients. Univariate analysis determined acute graft-versus-host disease and ABO-incompatibility as risk factors for TAM. Treatment consisted of withdrawal of calcineurin inhibitors and plasma exchange (PE). Response to PE was 64%. PE seems to be an effective therapeutic option that should be assessed in larger patient cohorts.     

Two patients with acute Guillain-Barré syndrome treated with different apheresis methods.

We treated 2 patients with severe acute Guillain-Barré syndrome (GBS) with different apheresis methods. Sera from these patients in the acute phase contained a high titer of immunoglobulin (Ig)G anti-GM1 ganglioside antibody. One was a 57-year-old female treated with immunoadsorption (IA). IgG anti-GM1 antibody titer was reduced from 1:102,400 to 1:6,400 measured by ELISA after 1 month. However, her residual deficit was severe. The other patient was a 43-year-old male treated with plasma exchange (PE). IgG anti-GM1 antibody was reduced from 1:3,200 to 1:400 after 1 session of PE. After 1 month, he could walk independently. The better prognosis of the latter was possibly because of the patient's younger age and the plasma exchange that might have reduced such pathogenic factors as antiganglioside antibodies at the early stage of GBS.     

A pilot study to compare the use of the Excorim staphylococcal protein immunoadsorption system and IVIG in chronic inflammatory demyelinating polyneuropathy.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune mediated neuropathy responding to immunomodulation with IVIG or plasma exchange (PE). We tested the efficacy and safety of selective immunoglobulin removal by Excorim immunoadsorption (IA) in a pilot trial in CIDP patients randomized to monthly IA or IVIG treatments for 6 months. Response rates at 2 and 6 months were greater with IA due to longer disease duration and greater disability at baseline in the patients receiving IVIG. IA appears to be a safe and efficacious therapy for patients with CIDP, but an appropriately powered clinical trial with stratification for disease duration is required.     

Rehabilitation of neuromyelitis optica (Devic syndrome): three case reports

We describe the inpatient clinical rehabilitation course of three patients with neuromyelitis optica (NMO; Devic syndrome). These patients had varying functional deficits. Each patient improved in several functional independence measures (FIM domains) but had minimal to no progress in other domains after acute rehabilitation stays between 1 and 1.5 mos. NMO is a severe central nervous system demyelinating syndrome distinct from MS, characterized by optic neuritis, myelitis, and at least two of three criteria: longitudinally extensive cord lesion, MRI nondiagnostic for multiple sclerosis, or NMO-IgG seropositivity. Persons with NMO may demonstrate improved function with rehabilitation efforts; though gains may be lost to relapse. Future immunomodulatory intervention may augment the benefits of rehabilitation.     

Relapsing or refractory idiopathic thrombotic thrombocytopenic purpura‐hemolytic uremic syndrome: the role of rituximab

Idiopathic thrombotic thrombocytopenic purpura–hemolytic uremic syndrome (TTP‐HUS) is a rare disease responsive to treatment with plasma exchange (PE) but with a high percentage of relapse or refractory patients. A severe deficiency of ADAMTS‐13 (<5% of normal activity), congenital or caused by an autoantibody, may be specific for TTP and it has been proposed that severe ADAMTS‐13 deficiency now defines TTP. B cells play a key role in both the development and the perpetuation of autoimmunity, suggesting that B‐cell depletion could be a valuable treatment approach for patients with idiopathic TTP‐HUS. This review of the literature focuses on the role of rituximab, a chimeric monoclonal antibody directed against CD20 antigen expressed by B lymphocytes, in patients with relapsing or refractory TTP‐HUS with or without ADAMTS‐13 deficiency, suggesting that rituximab may produce clinical remission in a significant proportion of patients. Rituximab therapy reduces plasma requirement and avoids complications related to salvage‐immunosuppressive therapy. In conclusion, rituximab provides an effective, well‐tolerated, and safe treatment option for patients with idiopathic TTP‐HUS, thus giving an alternative approach to the current treatment based on PE.     

Plasma exchange therapy for Kawasaki disease refractory to intravenous immunoglobulin

Kawasaki disease (KD) causes coronary artery lesions (CALs) in 600 to 800 Japanese children each year. As part of our recent search for effective treatments for KD cases refractory to intravenous immunoglobulin (IVIG), we have tried plasma exchange therapy (PE) in approximately 130 cases since 1995 till now. Multivariate analysis demonstrated that PE was effective approach for the prevention of CALs (odds ratio 0.052, p = 0.0012). We concluded that PE was a safe, effective prophylactic measure against CALs. Thus, PE should be performed at an early stage of this disease, by 10 days after onset, for KD cases refractory to IVIG.     

Lyme disease presenting as isolated acute urinary retention caused by transverse myelitis: An electrophysiological and urodynamical study

Several neurological manifestations of Lyme disease, both central and peripheral, have been described.¹ Reported here is a case of acute transverse myelitis related to a Lyme neuroborreliosis that presented with isolated acute urinary retention and no lower-extremity impairment. This case, documented by urodynamic and electrophysiological investigations, partially resolved after 6 weeks of intravenous ceftriaxone, affording the removal of the indwelling catheter. Alpha blocker therapy was needed for 3 months, until the complete normalisation of urodynamic and electrophysiological records. This case study indicates that whenever urinary retention is encountered associated with acute transverse myelitis or alone, the patient should be investigated for Lyme disease.     

Chronic thromboembolic pulmonary hypertension from the perspective of patients with pulmonary embolism

Summary

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but feared long‐term complication of acute pulmonary embolism (PE), although CTEPH may occur in patients with no history of symptomatic venous thromboembolism. It represents the most severe presentation of the so‐called ‘post‐PE syndrome’, a phenomenon of permanent functional limitations after PE caused by deconditioning after PE or ventilatory or circulatory impairment as a result of unresolved pulmonary artery thrombi. Because the post‐PE syndrome may occur in up to 50% of PE survivors, and CTEPH tends to have an insidious and non‐specific clinical presentation, CTEPH is often not diagnosed or diagnosed after a very long delay. Once the diagnosis is confirmed, the treatment of choice is pulmonary endarterectomy which effectively lowers the pulmonary vascular resistance and normalizes resting pulmonary artery pressures, leading to recovery of the right ventricle. When pulmonary endarterectomy is not technically feasible, balloon pulmonary angioplasty may be a potential acceptable alternative. Also, medical treatment may help to improve patient's symptoms and hemodynamics. Current studies are focusing on strategies for earlier CTEPH diagnosis after acute PE, as well as the most optimal treatment of inoperable patients. This review will focus on the epidemiology, risk factors, diagnosis and treatment of CTEPH from the perspective of the PE patient.

     

Intravenous immunoglobulin increases plasma viscosity without parallel rise in blood pressure

What is known and Objective: Intravenous immunoglobulin (IVIg) is a commonly used therapy for autoimmune disease, but may cause chronic hypertension and thrombosis. We determined whether: (i) IVIg systematically affects blood pressure in the short term; (ii) acute changes in plasma viscosity because of IVIg correlate with blood pressure effects; (iii) effects of IVIg on acute blood pressure are related to baseline blood pressure or hypertension status and (iv) IVIg influences plasma markers of inflammation, anticardiolipin antibodies and homocysteine as additional putative prothrombotic risk factors. Methods: Twenty adults with autoimmune neurological disease who received a course of IVIg were evaluated immediately before and after each infusion, on every day of the course. Blood pressure, pulse and the following haematological parameters were determined: plasma viscosity, erythrocyte sedimentation rate (ESR), C‐reactive protein (CRP), haematocrit, fibrinogen, interleukin‐6 (IL‐6), homocysteine and anticardiolipin positivity. Results: Intravenous immunoglobulin caused both acute and cumulative rises in plasma viscosity across a treatment course, but no concordant changes in blood pressure. There was also no correlation between individual blood pressure changes and viscosity, baseline blood pressure or hypertension status. Levels of IL‐6 rose across the course of therapy, but the acute‐phase reactants CRP and fibrinogen did not. One patient developed anticardiolipin antibodies during therapy. What is new and Conclusion: Individual courses of IVIg do not systematically raise blood pressure. Where IVIg is found to cause hypertension, this does not appear to be due to a direct effect of IVIg on plasma viscosity.     

Classification of MS and treatment strategy

Japanese patients with relapsing-remitting multiple sclerosis (RRMS) consists of two groups. One is opticospinal form (OSMS), in which major neurological symptoms derive from optic neuritis and myelitis, and the other is conventional form (CMS) that shares similar genetical and clinical features with western type of MS. OSMS patients tend to experience disease relapses more frequently with the resultant severer neurological deficit than CMS ones. Both OSMS and CMS patients are treated with intravenous high-dose methylprednisolone in acute exacerbations, and plasmapheresis may be considered for those who do not respond to repeated intravenous steroids. For prevention of disease relapse, interferon-beta is effective; however, patients with long spinal cord lesion extending over three vertebral segments should be followed up with caution, as this finding indicates a risk of treatment failure.     

Successful management of three patients with autoimmune thrombotic thrombocytopenic purpura with paradigm-changing therapy: Caplacizumab,steroids, plasma exchange,rituximab, and intravenous immunoglobulins (CASPERI)

Autoimmune thrombotic thrombocytopenic purpura (aTTP) is a severe disease caused by the production of autoantibodies against von Willebrand factor (vWF)-cleaving ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin-1 motifs; 13th member of the family). In 2018, caplacizumab was approved for the treatment of patients with acute aTTP in conjunction with plasma exchange (PE) and immunosuppressive therapy. Immunosuppressive standard of care includes mainly steroids whereas rituximab is usually reserved for refractory cases. We report three patients with a first acute episode of aTTP who were successfully treated with a paradigm-changing scheme including standard of care (caplacizumab, steroids and PE) plus upfront therapy with rituximab and intravenous immunoglobulins (CASPERI). Rituximab was added 1–4 days after diagnosis, when ADAMTS13 autoantibodies were detected and intravenous immunoglobulins were administered after performing PE using albumin as replacement solution. Successful outcome was observed in all three patients: platelet recovery (>150 × 10⁹/L) was observed after 3, 4, and 5 days from diagnosis; ADAMTS13 activity >5% and ADAMTS13 autoantibodies were negative after 14, 15, and 21 days from diagnosis. In conclusion, caplacizumab, steroids, PE (using fresh frozen plasma or albumin as replacement solution and adding intravenous immunoglobulins) plus upfront rituximab therapy was a safe and efficient combination to induce remission in case of acute aTTP.     

Treatment of polyarteritis nodosa and Churg-Strauss syndrome: indications of plasma exchanges

To define the most effective treatment for polyarteritis nodosa (PAN) and Churg-Strauss syndrome (CSS), we undertook 4 consecutive prospective therapeutic trials including 236 patients and tried to answer several important questions: Should cyclophosphamide (CYC) be given as the first-line treatment? What is the place of plasma exchanges (PE) in the treatment of systemic vasculitis? and does hepatitis B virus (HBV) related PAN require treatment? Our first randomized trial in 71 patients (1981-1983) compared the association of CYC with corticosteroids (CS) and PE to CS and PE, in order to evaluate the efficacy of CYC given as the first-line treatment to control disease activity and subsequent survival of PAN and CSS patients. Between December 1983 and December 1988, we conducted two trials simultaneously: one aimed at patients without HBV markers and the second at patients with HBV markers. In 78 patients without HBV markers, we compared prednisone and PE to prednisone alone as the initial therapeutic regimen. In 33 patients with PAN related to HBV, a new therapeutic strategy was applied as an alternative to long-term steroid and immunosuppressive therapy: short-term steroid therapy and PE were used to control the evolution of PAN and anti-viral therapy was administered to suppress the etiological agent of the vasculitis. In the last protocol including 56 patients and addressed to severe PAN without HBV markers or CSS we have shown that PE did not improve the prognosis and control of the disease. Twelve years after the beginning of the trials on PAN and CSS patients, we think that the therapeutic strategy should be as follows: In PAN without HBV and CSS: prednisone in association with CYC improves the control of the disease despite infectious side effects which may be reduced by better CYC dose adaptation. In PAN related to HBV: The first-line treatment should be the association of anti-viral agents and PE. This treatment was effective and cured a majority of patients within 2 to 3 months; half of them seroconverted. The length of HBV infection before its diagnosis, delay before initiation of treatment and previous immunosuppressive therapy led to a poor seroconversion rate. The role of PE in the treatment of systemic necrotizing vasculitis: PE are obviously useful in PAN related to HBV where immune complex deposition has been demonstrated. When PAN is not related to HBV and in CSS, even in severe cases, there is presently no argument supporting systematic administration of PE at the time of diagnosis.     

Establishment of a new sensitive assay for anti-human aquaporin-4 antibody in neuromyelitis optica

Neuromyelitis optica (NMO) is a devastating neurologic disease characterized by severe optic neuritis and transverse myelitis. Recently, its disease-specific serum autoantibody, NMO-IgG, was discovered with indirect immunofluorescence. However, the substrates of the immunofluorescence assay were not human but mouse brain tissues, which could influence the sensitivity and specificity of the antibody. The target antigen of NMO-IgG was recently identified as aquaporin-4 (AQP4) water channel protein, which is mainly expressed in brain and spinal cord. In the present study, we have established human cell lines that stably express human AQP4 and used these cells to detect and titrate anti-AQP4 antibody present in the sera of patients with NMO by immunofluorescence assay. The results were compared with those of the original NMO-IgG assay. We tested the sera from 10 patients with NMO, 10 with MS and five with other neurological disorders. Among the patients with NMO, six were NMO-IgG-positive. However, using the new anti-AQP4 antibody assay, we showed that eight patients with NMO including the six NMO-IgG-positives were positive for anti-AQP4 antibody. The staining pattern of AQP4-expressing cells treated with each serum of these eight NMO patients corresponded to that with a commercially available anti-AQP4 antibody. The antibody titer (maximum serum dilution for positive staining) ranged from 64x to 16,384x. The serum dilution titers were reproducible in blinded studies. In contrast, the patients with MS or other neurological disorders showed negative for anti-AQP4 antibody. Thus, the newly developed anti-AQP4 antibody assay appears to have a higher sensitivity for NMO than the original NMO-IgG assay and is expected to be useful for the diagnosis of NMO.