Therapeutic plasma exchange in patients with neurologic diseases: Retrospective multicenter study

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Transfusion and Apheresis Science 38 (2008) 109–115 intl.elsevierhealth.com/journals/tras

Therapeutic plasma exchange in patients with neurologic diseases: Retrospective multicenter study Leylagul Kaynar a, Fevzi Altuntas a,*, Ismet Aydogdu b, Burhan Turgut c, Ismail Kocyigit a, Sibel Kabukcu Hacıoglu d, Sevda Ismailogulları e, Nilda Turgut f, M. Ali Erkurt b, Ismail Sari d, Mehmet Oztekin a, Musa Solmaz a, Bulent Eser a, Ali Ozdemir Ersoy e, Ali Unal a, Mustafa Cetin a a

Erciyes Medical School, Department of Hematology and Apheresis Unit, 38039 Kayseri, Turkey b Inonu Medical School, Department of Hematology and Apheresis Unit, Malatya, Turkey c Trakya Medical School, Department of Hematology and Apheresis Unit, Edirne, Turkey d Pamukkale Medical School, Department of Hematology and Apheresis Unit, Denizli, Turkey e Erciyes Medical School, Department of Neurology, Kayseri, Turkey f Trakya Medical School, Department of Neurology, Edirne, Turkey

Received 20 August 2007; received in revised form 18 October 2007; accepted 11 November 2007

Abstract Therapeutic plasma exchange (TPE) is commonly used in many neurological disorders where an immune etiology was known or suspected. We report our experience with TPE performed for neuroimmunologic disorders at four university hospitals. The study was a retrospective review of the medical records of neurological patients (n = 57) consecutively treated with TPE between April 2006 and May 2007. TPE indications in neurological diseases included Guillain-Barre` Syndrome (GBS) (n = 41), myasthenia gravis (MG) (n = 11), acute disseminated encephalomyelitis (ADEM) (n = 3), chronic inflammatory demyelinating polyneuropathy (CIDP) (n = 1) and multiple sclerosis (MS) (n = 1). Patient median age was 49; there was a predominance of males. Twenty-two patients had a history of other therapy including intravenous immunoglobulin (IVIG), steroid, azothioprin, and pridostigmine prior to TPE. Another 35 patients had not received any treatment prior to TPE. All patients were classified according to the Hughes functional grading scores pre- and first day post-TPE for early clinical evaluation of patients. The TPE was carried out 1–1.5 times at the predicted plasma volume every other day. Two hundred and ninety-four procedures were performed on 57 patients. The median number of TPE sessions per patient was five, and the median processed plasma volume was 3075 mL for each cycle. Although the pre-TPE median Hughes score of all patients was 4, it had decreased to grade 1 after TPE. While the pre-TPE median Hughes score for GBS and MG patients was 4, post-TPE scores were decreased to grade 1. Additionally, there was a statistically significant difference between post-TPE Hughes score for GBS patients with TPE as front line therapy and patients receiving IVIG as front line therapy (1 vs. 3.5; p = 0.034). Although there was no post-TPE improvement in Hughes scores in patients with ADEM and CIDP, patients with MS had an improved Hughes score from 4 to 1. Mild and manageable complications such as hypotension and hypocalcemia were also observed. *

Corresponding author. Tel.: +90 532 658 80 50; fax: +90 352 437 93 48. E-mail address: [email protected] (F. Altuntas).

1473-0502/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.transci.2007.11.002

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TPE may be preferable for controlling symptoms of neuroimmunological disorders in early stage of the disease, especially with GBS. Ó 2008 Elsevier Ltd. All rights reserved. Keywords: Therapeutic plasma exchange; Guillain-Barre` Syndrome (GBS); Myasthenia gravis (MG); Acute disseminated encephalomyelitis (ADEM); Chronic inflammatory demyelinating polyneuropathy (CIDP); Multiple sclerosis (MS)

1. Introduction Therapeutic plasma exchange (TPE) is a wellestablished therapeutic procedure commonly used in many disorders where an immune etiology was known or suspected. TPE removes antibodies and substances leading to immune mediated disorders; it is possible that TPE may help control the symptoms of the disease. Immune etiology has been implicated in the pathogenesis of some neurologic diseases, i.e., GuillainBarre` syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP) and myasthenia gravis (MG), multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM) [1,2]. TPE is often used alone or in combination with other treatment options as a frontline therapy in these neurological disorders [3–5]. Other treatment modalities, including intravenous immunoglobulin (IVIG) for patients with GBS, pyridostigmine for MG, azathioprine for MG and MS and corticosteroids for MS, ADEM, CIDP have been used to control disease [4,6–8]. Studies indicate that there may be potential complications with TPE therapy [9,10]. However, because of limited clinical trials there is scant data regarding the short-term and long-term efficacy and safety of TPE. This retrospective study was performed as an analysis of our experience with TPE with regard to early treatment outcomes and procedural complications in adult patients with neurological disorders. 2. Patients and methods This is a retrospective analysis of neurologic diseases requiring TPE in four University Hospitals between April 2006 and May 2007. The list of patients was obtained from the TPE log-book of the apheresis units in our facility. The medical records of neurology departments and apheresis units were reviewed with regard to patient demographic data, i.e., diagnosis, age, sex. We also collected clinical histories including initial presentation, concomitant diseases, drug intake, treatment (therapeutic plasma exchange as

front line treatment and second/third line treatment, adjuvant and/or alternative agents, i.e., corticosteroid, IVIG, pyridostigmine and immunosuppressive drugs), procedural complications, and outcome. All patients were classified according to the Hughes functional grading scores for clinical evaluation pre-TPE and first day post-TPE. In the Hughes functional grading score, grade 0; no sign or symptom, grade 1; minor signs or symptoms of neuropathy but capable of running, grade 2; able to walk without support of a care minimum 10 m but incapable of running, grade 3; able to walk with a cane, appliance, or support for 10 m, grade 4; confined to bed or chair bound (not able to walk with a support for 10 m); grade 5; requiring assisted ventilation and grade 6; dead [11]. TPE was carried out at the predicted plasma volume for 1–1.5 times every other day using Fresenius Com.Tec apheresis devices (Fresenius AG, Germany). Plasma volumes were calculated for each patient using the patient’s body surface area (calculated using height and weight), sex, and hematocrit. Albumin or fresh frozen plasma (FFP) was used as the replacement product. Patients underwent TPE using a 16 G backeye access needle in an antecubital fossa vein; a 20 G venous cannula was placed in the opposite arm for the return line. Central venous catheters (12 F, Arrow) were used in patients with an inadequate peripheral venous access. In order to avoid severe hypocalcaemia during the procedure, all patients received an intravenous infusion of 10% calcium gluconate (30 mL), providing up to 819 mg of calcium. Senior apheresis technicians performed all procedures. Vital signs were monitored at the beginning and end of each procedure, and patients were monitored for adverse events during the apheresis procedures. Written informed consent was obtained from all patients after procedural risks were explained in detail before each procedure. 3. Statistics Data were expressed as median and range. Data were analyzed with an SPSS program (SPSS 13.0,

L. Kaynar et al. / Transfusion and Apheresis Science 38 (2008) 109–115

Inc., Chicago, IL) which compared differences in Hughes scores for patients with GBS and MG both pre- and post-TPE using the Wilcoxon Signed Ranks Test. The Mann–Whitney U-test was applied to determine the differences between variables which were not within normal distribution, e.g., Hughes scores pre- and post-TPE for all patients, GBS patients treated with TPE as second/third line treatment (received IVIG before TPE), GBS patients treated with TPE as front line therapy, time to start TPE and the number of TPE procedures in GBS patients treated with TPE as second/third line treatment (received IVIG before TPE) and in GBS patients treated with TPE as front line therapy. Statistical significance was set at p < 0.05.

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prine (3 mg/kg/d) plus pyridostigmine (180 mg/d) plus prednisolone (1 mg/kg/d). The other 35 patients had not received any treatment before TPE. Treatment modalities used are shown in Table 1. 4.3. Therapeutic plasma exchange

4. Results

Of the 57 patients, 35 were treated with TPE as front line therapy; 22 patients received TPE as second/third line therapy. Fifty-seven patients received a total of 294 procedures. The median number of TPE sessions per patient was 5 (range 3–12). The median processed plasma volume was 3075 mL (range = 2300–4550 mL) for each cycle. Human albumin was used as a replacement fluid in 235 procedures (n = 44) and FFP was used in 69 procedures (n = 13).

4.1. Demographic data

4.4. Outcome

Of the 57 patients, 42 (74%) were men and 15 (26%) were women. The median age was 49 (range: 21–67) years. Patients’ demographic data are shown in Table 1.

Overall response to TPE was seen in 47/57 (82%) patients. No response to TPE was seen in 10 patients (18%). Median time to achieve a response was 10 days and 5 procedures (range = 2–24 days, and 3–12 procedures). Although the median Hughes score of all patients was 4 (range = 3–5) prior to TPE, it decreased to a median grade 1 (range = 0– 5) after TPE (p < 0.0001).

4.2. Therapies prior to TPE There were 22 patients who had a history of other therapy including IVIG, steroid, azathioprine, and pyridostigmine prior to TPE. Nine patients had received IVIG (2 g/kg/d, 1 day), seven prednisolone (1 mg/kg/d), two pyridostigmine (180 mg/d), one azathioprine (3 mg/kg/d), one azathioprine (3 mg/ kg/d) plus prednisolone (1 mg/kg/d), two azathio-

4.5. Patients with Guillain-Barre` syndrome There were 41 patients with GBS: 32 males (median age, 50 years; range = 17–82 years. Eight patients on TPE as second line therapy had received

Table 1 Patient characteristics Patient/treatment

GBS (n = 41)

MG (n = 11)

ADEM (n = 3)

MSa (n = 1)

CIDP (n = 1)

Total (n = 57)

Age (years) (median) Male/female (n) TPE as front line therapy (n) TPE as second/third line therapy (n)

50 32/9 33 8

49 7/4 1 10

43 3/0 0 3

25 0/1 1 0

59 0/1 0 1

49 42/15 35 22

Treatment history prior to TPEb IVIG Steroid Pyridostigmine Azothiopurin Azathioprine + steroid Azathioprine + pyridostigmine + steroid

8 0 0 0 0 0

1 3 2 1 1 2

0 3 0 0 0 0

0 0 0 0 0 0

0 1 0 0 0 0

9 7 2 1 1 2

GBS = Guillain-Barre` syndrome, MG = myasthenia gravis, ADEM = acute disseminated encephalomyelitis, and MS = multiple sclerosis. a Acute central nervous system inflammatory demyelinating disease, CIDP = chronic inflammatory polyradiculoneuropathy. b All patients had received IVIG ± steroid ± azothioprin ± pridostigmine and non-responsive to these therapies prior to TPE.

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Table 2 Results of GBS patients according to Hughes scores

Pre-TPE (n = 41) Post-TPE (n = 41)

Grade 0 (n)

Grade 1 (n)

Grade 2 (n)

Grade 3 (n)

Grade 4 (n)

Grade 5 (n)

Grade 6 (n)

Median score

0 4 (10%)

0 19 (46%)

0 7 (17%)

8 (20%) 5 (12%)

24 (58%) 3 (7%)

9 (22%) 3 (7%)

0 0

4 1

IVIG as front line therapy, but were not responsive to this treatment before TPE. Other 33 patients received TPE as front line therapy. In GBS patients treated with TPE as second line therapy, the median time to initiation of TPE procedure was 23 days (range = 7–35 days); in GBS patients treated with TPE as front line therapy median time to TPE initiation was 2.5 days (range = 1–15 days) (p < 0.0001). The median number of TPE was 5 (range = 3–8). A response to TPE was seen in 35/41 (85%) patients with GBS. There was no response to TPE in 6 patients (15%). Pre-TPE median Hughes score of all GBS patients was 4 (range = 3–5); this decreased to median grade 1 (range = 1–5) p < 0.0001) after TPE (Table 2). There were statistical differences in terms of Hughes score to TPE between GBS patients treated with TPE as front line therapy and GBS patients treated with TPE as second line therapy. These patients received IVIG as front line therapy. Median Hughes score 1 vs. 3.5, respectively (p = 0.034). Although 88% (21/24) of patients with grade 4 improved with TPE [grade 1 (n = 12), grade 2 (n = 6) and grade 3 (n = 3)], three patients (12%) with grade 4 were non-responsive to TPE. Additionally, 67% (6/9) of patients with grade 5 responded to TPE [grade 1 (n = 3), grade 2 (n = 1) and grade 3 (n = 2)]. However, three patients with grade 5 were non-responsive. All patients with grade 3 did respond to TPE [grade 0 (n = 4) and grade 1 (n = 4)]. 4.6. Patients with myasthenia gravis There were 11 patients with MG. Seven patients were male and median age was 49 years (range = 18–72 years). Ten patients who had TPE as second/third line therapy had received pyridostigmine, prednisolone and/or azathioprine prior to

TPE; they were non-responsive to therapy before TPE. There was only one patient treated with TPE as front line therapy. Median time to initiation of TPE procedure was 18 days (range = 1–35 days) in MG patients. Median number of TPE was 5 (range = 3–12). A response to TPE was seen in 100% of patients. Median cycles of TPE were five (range = 3–12). Although the pre-TPE Hughes score of all MG patients was median 4 (range = 3–5), post-TPE score decreased to grade 1 (range = 0–2) (p = 0.003) (Table 3). The Hughes scores in patients with MG crisis improved at least two grades in a short time after TPE therapy. 100% (5/5) of patients with grade 5 improved with TPE [grade 0 (n = 2), grade 1 (n = 1) and grade 2 (n = 2)], all patients with grade 4 improved with TPE [grade 1 (n = 2) and grade 2 (n = 1)], and all three patients with grade 3 were classified as Hughes grade 1 after TPE.

4.7. Other patient groups There were 5 patients diagnosed as ADEM (n = 3), CIDP (n = 1) and MS (n = 1). Their median age was 43 years (range = 25–59 years); three patients were female. All patients received IVIG and/or steroid therapy as front line therapy and were non-responsive to it prior to TPE. A response to TPE was seen in 1/5 (20%) patient. No response to TPE was seen in 4 patients (80%). Pre-TPE Hughes score of patients with ADEM was median 5 (range = 5). There was no post-TPE improvement in Hughes scores (median = 5). Additionally, Hughes score in CIDP patient was not changed after TPE (Hughes score = 4). One patient with acute central nervous system inflammatory demyelinating disease of MS was classified as Hughes grade 4 before TPE. This patient’s Hughes score

Table 3 Results of MG patients according to Hughes scores

Pre-TPE (n = 11) Post-TPE (n = 11)

Grade 0 (n)

Grade 1 (n)

Grade 2 (n)

Grade 3 (n)

Grade 4 (n)

Grade 5 (n)

Grade 6 (n)

Median score

0 2 (18%)

0 6 (55%)

0 3 (27%)

3 (27%) 0

3 (27%) 0

5 (46%) 0

0 0

4 1

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was decreased from grade 4 to 1 after median five procedures (range = 5–7). 4.8. Adverse events and complications In no case was the process terminated because of adverse events. Complications were mild and consisted of hypotension and hypocalcemia. Hypotensive episodes occurred in six patients and hypocalcemia was observed in five patients. There was no catheter related complication such as hematoma or infection. 5. Discussion TPE is often used alone as front line therapy or as adjuvant and/or alternative therapy in neurologic disease, i.e., GBS, MG and CIDP [3–5]. In addition, TPE may be used for treatment of other neurologic disorders, such as MS and ADEM [2,3]. GBS is an immune mediated neuropathy characterized by the acute onset of symmetric progressive motor weakness with areflexia and sensory deficits [12]. It is the main cause of acute polyneuropathy [13]. IVIG or TPE therapies are used in patients with severe GBS [14]. Several randomized studies have been performed to determine the efficacy and safety of TPE in GBS [15–18]. Plasma Exchange/Sandoglobulin Guillain-Barre´ Syndrome Trial Group performed an international multicentre, randomized controlled trial to find out whether IVIG (0.4 g/kg daily for 5 days) is equivalent or superior to TPE (five 50 mL/kg exchanges over 8–13 days) in the treatment of GBS (n = 383) and whether TPE followed by IVIG is equivalent or superior to the single treatment. They compared TPE with IVIG, and with a combined regimen of TPE followed by IVIG. There was no difference in terms of clinical outcome between the groups [18]. In addition, the Cochrane Systematic meta-analysis reported that TPE was the only treatment for GBS found to be superior to supportive treatment [19]. Furthermore, TPE was more beneficial when applied within the first 7 days of disease, although it was still effective when performed within the first month [19]. There are, however, no adequate randomized controlled trials to determine whether TPE improves the long-term outcome for disease. In the present study, the most common neurological disease treated with TPE was GBS (41/57; 72%). Of patients, 85% (35/41) improved after a median of 5 TPE sessions (range = 3–8). The Hughes score in GBS patients

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was improved from median 4 to 1 after TPE (p < 0.0001). There were statistical differences in terms of the Hughes score to TPE between GBS patients treated with TPE as front line therapy and GBS patients treated with TPE as second line therapy (Median Hughes score 1 vs. 3.5) (p = 0.034). However, further randomized prospective clinical trials need to be conducted with a larger series of patients in order to determine whether results of treatment improve when TPE is performed in early stages of symptomatic disease, and whether TPE improves the long-term outcome. Myasthenia gravis is a potentially serious but treatable organ specific autoimmune disorder characterized by weakness and fatigue of the voluntary muscles; this is due to autoantibodies against the nicotinic acetylcholine receptor (AchR) on the postsynaptic membrane at the neuromuscular junction [20]. TPE appears to be just as beneficial as IVIG therapy in patients with MG [21,22]. One possible explanation is the removal of the AchR antibody or antibodies directed against a different antigenic determinant of the neuromuscular junction [2]. Some non-randomized studies report that TPE is beneficial in the short-term outcome of disease [23–25]. Additionally, Myasthenia Gravis Clinical Study Group conducted a trial to assess the efficacy and tolerance of IVIG or TPE (three times) in MG exacerbation and to compare two doses of IVIG (0.4 g/kg daily for 3 days vs. for 5 days). They reported that there was no difference in the primary outcome measure between TPE and IVIG groups and similar efficiency between the IVIG groups [22]. However, there is no adequate randomized, controlled trial to determine whether TPE improves the short-term outcome as well as long-term outcome for myasthenia gravis [26]. In this study, all of patients with MG responded to TPE. The Hughes scores in patients with myasthenic crisis were improved at least two grades shortly after TPE. The median time to achieve a response was 5 procedures (range = 3–12 procedures). However, the roles of TPE in terms of short-term and longterm outcome need to be further investigated with randomized prospective clinical trials conducted with a larger series of patients. ADEM is usually a monophasic inflammatory demyelinating disease process that affects the brain and spinal cord. The typical presentation is that of multifocal neurologic disturbance accompanied by change in mental status. The pathogenesis of ADEM is thought to be disseminated multifocal inflammation and patchy demyelination associated with auto-

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immune mechanisms in the central nerves system [27]. There are some case reports in which TPE could be effective after corticosteroid failure [28,29]. Keegan reviewed 59 neurologic patients treated with TPE for severe attacks of central nervous system demyelination. In this review, 10/59 of patients had ADEM; 4/10 patients had moderate to marked improvement after TPE [30]. In the present study, there was no significant post-TPE improvement in neurologic function in patients with ADEM. However, it is difficult to say that TPE is effective or non-effective in ADEM because the number of patients with ADEM is very few. Acute central nervous system inflammatory demyelinating diseases of MS commonly result in acute neurological disability [31]. CIDP is of insidious onset leading to prolonged and progressive disability and even death [32]. In the present study, only one patient had central nervous system inflammatory demyelinating diseases of MS and the postTPE Hughes score was decreased from 4 to 1. However, the patient with CIDP did not improve with TPE. There were not enough patients to determine whether TPE is beneficial in the treatment of patients with CIDP and MS. Therefore, the roles of TPE need to be further investigated with larger series of patients. It is reported that TPE is a relatively safe method of treatment, providing it is performed by experienced staff and used for appropriate indications with all necessary precautions [9,10,33,34]. The most reported complications are hypotension, hypocalcemia, catheter dysfunction, urticaria, bleeding, dysrythmia [9,10]. Major complications such as sepsis requiring vasopressor support, anaphylaxis, severe hypotension, acute pulmonary edema, myocardial infarction, and death are reported in 1.6– 22% of patients [9,10,35,36]. In the present study, there was no major complication due to the procedure or catheter used for TPE during the procedure. The complications consisted of hypotension (n = 6) and citrate related hypocalcemia (n = 5). All of the hypotensive episodes and hypocalcemia were resolved briefly after intravenous infusion of saline or further calcium infusion. These complications were mild. In conclusion, TPE is an effective treatment option for patients with GBS and MG. In addition, TPE may control disease progression in patients with GBS, especially when performed in the early stages of the disease. Further, TPE seems to be a relatively safe procedure. However, the role of TPE

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