57858ournal ofNeurology, Neurosurgery, and Psychiatry 1994;57:578-581 Immunoadsorption therapy for myasthenia gravis J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.5.578 on 1 May 1994. Downloaded from Noritoshi Shibuya, Takeshi Sato, Mitsuhiro Osame, Toshihiko Takegami, Shizuki Doi, Sachiko Kawanami Abstract neurological disorders. A major disadvantage The results of a multicentre trial were of currently available plasma exchange proce- analysed to evaluate the efficacy of dures is the non-selective removal of essential immunoadsorption therapy for severe plasma components, necessitating a supply of generalised myasthenia gravis. Twenty plasma products to serve as a substitute fluid. patients with myasthenia gravis who were Plasma exchange is costly and carries serious concurrently receiving high dose pred- risks of anaphylactic reactions and viral infec- nisolone and azathioprine therapy were tions.6 9 10 It is preferable to remove pathogenic treated with an affinity-type adsorbent, substances from the circulation selectively. A using tryptophan-linked polyvinyl alco- specially designed affinity-type immunoadsor- hol gel (IM-TR), according to a standard- bent to selectively remove AChR antibodies ised treatment protocol. The 20 patients has been developed."' 12 This material is a syn- received five adsorption treatments within thetic resin consisting of tryptophan-linked a period of 10 days. In 11, pronounced polyvinyl alcohol gel (IM-TR). It adsorbs a improvement of myasthenic weakness large number of the AChR antibodies through was seen and long-term remission was hydrophobic interaction and rapidly improves maintained. The treatment was espe- myasthenic weakness.13'6 cially effective in patients with thymic The present study was carried out at six hyperplasia. Circulating acetylcholine neurological hospitals, according to a stan- receptor (AChR) antibodies were dardised treatment protocol to assess the clin- reduced by about 60% by treating one ical usefulness of IM-TR therapy in cases of plasma volume. There was no difference severe myasthenia gravis. in the rate of removal of the AChR anti- bodies between patients with thymic hyperplasia and patients with thymoma. Patients and methods Department of included in this study had severe gen- Neurology, Kawatana No serious complications occurred dur- Patients National Hospital, ing 100 procedures. It was concluded that eralised myasthenia gravis diagnosed by typi- Nagasaki, Japan the inmunoadsorption therapy with IM- cal clinical signs and raised titres of antibodies N Shibuya TR is useful in controlling symptoms in to AChR (more than 0-5 nmol/l bungarotoxin Department of patients with severe myasthenia gravis binding); patients were in myasthenic crisis http://jnnp.bmj.com/ Neurology, Juntendo University, Tokyo, who are otherwise unresponsive. with rapid deterioration within less than two Japan weeks. Criteria for exclusion were chronic T Sato (7 Neurol Neurosurg Psychiatry 1994;57:578-581) severe and stable myasthenia gravis; multiple Third Department of changes in the immunosuppressive medica- Internal Medicine, tion before treatment; and malignant (inva- Kagoshima University, Circulating antibodies to the acetylcholine sive) thymoma as determined by a are in serum in diagnosis of the thymus gland. Kagoshima, Japan receptor (AChR) detectable pathological on September 27, 2021 by guest. Protected copyright. M Osame 85%-90% of patients with generalised myas- Twenty patients, range 15-65 years (five Department of thenia gravis.'-3 Most AChR antibodies in IgG men, 20 women), have been treated with the Neurol6gy, Nagoya were acetyl- National Hospital, bind to the main immunogenic region of the a immunoadsorption. All receiving Aichi, Japan subunit of the AChR, and cause AChR degra- cholinesterase inhibitors. The dose was kept T Takegami dation secondary to cross-linking and modu- constant during the study. All patients had to Department of lation.2-5 Plasma exchange has been shown to have undergone thymectomy at least three Neurology, Sapporo induce a recovery from myasthenic months before the study. Their thymic histol- Minami National rapid Hospital, Hokkaido, weakness in association with the decline of the ogy showed thymic hyperplasia in 13, thy- Japan AChR antibodies." At a consensus develop- moma in six, and was indeterminate in one S Doi ment conference, plasma exchange was con- (table 1). The histological diagnoses were First Department of sidered effective in the management of certain obtained from the surgical pathologists' Internal Medicine, Fukuoka University, Fukuoka, Japan Table 1 Analysis of relation between clinicalfeatures and outcome ofimmunoadsorption therapy Kawanami S Removal of Correspondence to: Sex Duration Time before Thymic histology* AChR Ab Dr N Shibuya, Departnent No of ofillness thymectomy on day 10 of Neurology, Kawatana patients Age M F (y) (y) Hyperplasia Thymoma (%) National Hospital, 2005-1 Effect Shimogumigo, Kawatana, Pronounced 11 40(13) 2 9 9(5) 4(3) 9 1 58(9) Higashisonogi-gun, Poor and 9 36(17) 3 6 5(5) 3(4) 4 5 65(14) Nagasaki, 859-36 Japan. unresponsive Received 13 April 1993 p Value NS NS NS NS <0 05 NS and in revised form 7 June 1993. Values are means (SD); NS = non-significant; p values are one-tailed. Accepted 14 July 1993 *Thymic histology was unknown in one patient. Immunoadsorption therapyfor myasthenia gravis 579 reports. The thymoma were of both lympho- laboratory findings were obtained at 0, 4, 11, J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.5.578 on 1 May 1994. Downloaded from cytic and epithelial types. In the non-tumour 14, and 28 days according to the study proto- cases the thymus showed hyperplasia of col. The observation period was extended up lymph follicles. to 42 days if no change in the treatment had Immunosuppressive treatment with aza- occurred. The effects of immunoadsorption thioprine and prednisolone was instituted on were also analysed in relation to clinical fea- day 0. Azathioprine was given at a dose of 3 tures such as age, sex, duration of illness, time mg/kg body weight during the first week and before thymectomy, and thymic histology. 2-5-2 mg/kg body weight for the subsequent The clinical and electrophysiological exam- four weeks (if this dose was not tolerated it inations were performed by the local neuro- was reduced to 2-1P5 mg/kg body weight). logical investigator. The examining Prednisolone was given at a dose of 1-5 mg/kg neurologists were blind as to plasma exchange body weight for the first two weeks, and treatments. All laboratory investigations that 1 5 mg/kg body weight on alternate days would allow the neurological investigator to thereafter. know about the treatment were kept separate Immunoadsorption with IM-TR was car- and were only known to the physician per- ried out on-line with a plasma separator con- forming plasma exchange. Raw data were sisting of a cellulose diacetate membrane. The listed in the study protocol and sent to the blood flow was kept at 70-80 ml/min, and study coordinator for statistical analysis. the transmembrane pressure was less than Because this study was designed as an 40 mm Hg. The flux rate of the filtration (the open, one-armed treatment trial, all compar- flow rate at the IM-TR column) was 20 isons were within groups. Changes from base- ml/min. Adsorption was performed with line observed at 11 days and 28 days after about one plasma volume (an average of 2300 treatment were also compared to analyse the ml of plasma) on days 1, 3, 5, 8, and 10, for a time profile, because the main response vari- total of five treatments. Heparin was used as able in evaluating efficacy was the change in an anticoagulant at an initial dose of 2000 the clinical scores adjusted by the pre-treat- units, then 2000 units/hour during the period ment value. The baseline employed was the of perfusion. Fluids contained in the system observation immediately before the first were reinfused into the patient at the end of immunoadsorption treatment. Statistical the procedure. No plasma proteins were analysis was by Student's t test or x2 test. given. Results are expressed as means (SD). Clinical assessment was based on clinical muscle testing (the myasthenia gravis score of Besinger and Toyka17), the titre of antibodies Results to AChR (a standard immunoprecipitation Pronounced and rapid recovery from myas- assay with solubilised human receptor'), elec- thenic weakness was noted in 11 patients after tromyographic analysis of the neuromuscular a series of immunoadsorption treatments, but transmission block, and side effects if any. in the others the clinical state showed little Briefly, a four-step system for grading muscle change despite a substantial dectease in strength was used (ranging from 0 = normal AChR antibody titre (table 1). Nine of 13 http://jnnp.bmj.com/ to 3 = severe weakness). In each patient, five patients with thymic hyperplasia improved, test items for muscles of the limbs and trunk although only one of six patients with thy- and three test items for the oropharyngeal moma benefited (table 1). The improvement muscles were examined. All items were given was stable in nine of them for at least 32 days the same weight. The myasthenia gravis score after termination of the immunoadsorption. was calculated as the sum of the grades in The clinical effect was significantly correlated each item divided by the number of the items with thymic histology (tables 1 and 2), but no tested. For each patient, the treatment was correlation was noted with age, sex, duration on September 27, 2021 by guest. Protected copyright. judged to be efficacious if the myasthenia of illness, and time before thymectomy (table gravis score on day 11 was more than 35% 1). Percentage improvement of the mean higher than the pretreatment value. To esti- myasthenia gravis score was 39% on day 1 1 mate the neuromuscular transmission block and 35% on day 28 in patients with thymic quantitatively, the decline in the amplitude of hyperplasia, whereas it was 15% and 1 % in successive responses to repetitive nerve stimu- those with thymoma (table 2).