Journal of Clinical Apheresis 29:171–177 (2014)
Case Report Therapeutic Plasma Exchange in Neuromyelitis Optica: A Case Series Shanna M. Morgan,1* Nicole D. Zantek,1 and Adam F. Carpenter2 1
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 2 Department of Neurology, University of Minnesota, Minneapolis, Minnesota Neuromyelitis optica (NMO) is a relapsing inflammatory disease of the central nervous system that predominantly affects the spinal cord and optic nerves. The clinical hallmark of the disease is a step-wise deterioration of visual and spinal cord function. This study reviews patients with steroid resistant relapsing NMO presenting for therapeutic plasma exchange (TPE) at our institution from December 2005 to December 2012. A total of five patients were treated with single volume TPE. Both subjective and objective clinical response to TPE was estimated by three different sources (the patient, a Transfusion Medicine physician, and the treating Neurologist) with the patient and Transfusion Medicine physician’s final assessment of response made at the time of the last TPE in the series and the treating neurologist’s assessment of response made at the time of the next neurological exam after the last TPE. A total of 17 TPE series were performed with the average course of therapy being three series (ranged 1–5) with five TPE (ranged 3–7) per series. All patients demonstrated improvement with each series of TPE and all procedures were well tolerated with only transient and well-described reactions all of C 2013 which were successfully resolved with minor or no sequelae. J. Clin. Apheresis 29:171–177, 2014. V Wiley Periodicals, Inc.
Key words: apheresis; Devic’s disease; optic neuritis
INTRODUCTION
Neuromyelitis optica (NMO) is a severe inflammatory disease that typically affects the spinal cord and optic nerves, while sparing the brain [1]. The clinical hallmark of the disease is a relapsing-remitting course of optic neuritis and myelitis resulting in a step-wise deterioration of visual and neurologic function [2]. Clinical features are diverse and may include the following: unilateral or bilateral visual field deficits, ocular pain, severe paraplegia, sensory loss below the lesion, bowel and bladder dysfunction, paroxysmal tonic spasms of the trunk and limbs, intractable hiccups, nausea, and Lhermitte’s phenomenon [3–5]. Historically, NMO has been considered a rare disease; however, this is likely due to under-diagnosis, mostly commonly from a misdiagnosis of multiple sclerosis (MS) [6]. NMO prevalence in the United States is estimated to be approximately 4,000 to 8,000 patients [7]. Diagnostic frequency and accuracy has undoubtedly increased since the recent development of anti-aquaporin 4 antibody (NMO-IgG) as a serologic marker of NMO. Aquaporin 4 (AQP-4) is a protein expressed on the astrocyte foot processes that is involved in water homeostasis throughout the central nervous system [4,8,9]. Immunopathological studies C 2013 Wiley Periodicals, Inc. V
indicate NMO to be an acute antibody-mediated inflammatory process involving AQP-4 [4]. Loss of AQP-4 leads to edema, axonal injury, demyelination, necrosis, and cavitation [8,9]. Serologic testing for NMO-IgG can aid in the diagnosis and is incorporated into the diagnostic criteria put forth by Wingerchuk et al. [10]. The diagnostic criteria state that a patient must have (1) optic neuritis, (2) acute myelitis, and (3) at least two of the three following elements: (a) MRI showing contiguous spinal cord lesions extending three or more vertebral segments, (b) non-diagnostic brain MRI for multiple sclerosis, or (c) NMO-IgG seropositive status [10]. NMO-IgG seropositivity is reported to have a sensitivity of 76% and a specificity of 94% and is a strong predictor of a relapsing course [8,10]. Evidence suggests that there are two major clinical courses of NMO, monophasic and relapsing [11]. The *Correspondence to: Shanna M. Morgan, Department of Laboratory Medicine and Pathology, Division of Transfusion Medicine, D242 Mayo Building, MMC 609, 420 Delaware Street S.E., Minneapolis, MN 55455. E-mail: [email protected] Received 3 May 2013; Accepted 20 September 2013 Published online 17 October 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jca.21304
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monophasic form presents as a bilateral optic neuritis and transverse myelitis storm, as they occur simultaneously or within days of each other. Although the short term prognosis is worse in patients with monophasic NMO, the long-term prognosis is better because these patients typically do not have recurrent attacks leading to further disabilities [1]. Monophasic NMO patients are younger individuals, with an equal sex ratio, and overall they have a lower percentage of NMO-IgG positivity as compared to the relapsing group [1,12]. Relapsing NMO is by far more common, accounting for 80% or more of cases [1,4,6]. These patients typically present in the fourth or fifth decade, have a strong predilection for females at a ratio of approximately 7:1, and have an overall higher percentage of NMO-IgG positivity [6,7]. These patients have a rather unpredictable clinical course with recurrent attacks of optic myelitis and transverse myelitis at intervals of months to years [11]. Severe cervical myelitis with possible respiratory failure and death is a major health concern in relapsing NMO, comprising the majority of the 20% of patients who die within the first 5 years [3,11,13]. Once a diagnosis of NMO is made, the therapeutic goals for these patients include quickly preventing further production of the offending antibody with immunosuppressive therapy. In patients who do not respond to pharmacotherapy, therapeutic plasma exchange (TPE) may be beneficial in both the acute setting and in the preventative setting [8,14–23]. The benefits are likely through removal of circulating pathogenic immune or inflammatory substances [24]. We present a retrospective study of five patients with relapsing NMO who were treated with TPE as acute immunotherapy for NMO relapses. In addition, two of these patients were treated with additional maintenance TPE (mTPE) in between attacks as preventative therapy. MATERIALS AND METHODS Patients
A retrospective review was performed on patients with steroid resistant relapsing NMO presenting for TPE at our institution from December 2005 to December 2012. Informed, written consent to use the patient’s medical record for research was obtained at time of first TPE and this study was approved by our institutional review board. The five patients reviewed in this study were diagnosed with NMO based on criteria proposed by Wingerchuk et al. in 2006 [10]. Additional inclusion criteria for this study required that the patient be experiencing an acute or subacute worsening of neurological symptoms for greater than 24 h, without evidence of new infection or other underlying acute medical condition, and deemed by a neurologist to be an acute NMO attack. Journal of Clinical Apheresis DOI 10.1002/jca
NMO-IgG Serology
NMO-IgG serologies were tested at the Mayo Medical Laboratories, Mayo Clinic, Rochester, MN. TPE and mTPE Protocol R
Single volume TPE were performed with a CobeV Spectra cell separator (TerumoBCT, Lakewood, CO) using 5% albumin for replacement fluid. Anticoagulant Citrate Dextrose Solution A (ACD-A) was used for extracorporeal anticoagulation at an anticoagulant to whole blood ratio of 1:13. Prophylactic intravenous 10% calcium gluconate infusion was given through the return line over the duration of the procedure to offset the effects of the citrate-based anticoagulant. The rate of calcium gluconate solution infusion ranged from 800 mg/L for 5% albumin replacement or 1,000 mg/L for plasma replacement with the rate increased up to a maximum of 2,400 and 3,000 mg/L, respectively, in the presence of citrate toxicity symptoms (paresthesia, tingling, muscle cramps, nausea) or ionized calcium levels below the reference range. Clinical Assessments
We evaluated the effect of TPE on the degree of recovery from NMO relapse as follows. The time of onset and primary symptom(s) of the relapse were identified from the treating neurologists hospital or clinic notes. Both subjective and objective clinical response to TPE was estimated by three different sources (the patient, a Transfusion Medicine physician, and the treating Neurologist). With each TPE, an apheresis nurse and physician evaluated each patient. The patient and Transfusion Medicine physician’s final assessment of response was made at the time of the last TPE in the series. The treating neurologist’s assessment of response was made at the time of the next neurological exam after the last TPE. Response was estimated as degree of improvement in the primary relapse symptoms, similar to Keegan et al 2002 [25]: “no improvement” (no improvement in neurological symptoms or function), “mild improvement” (improvement in symptoms or exam, but with residual impairments in daily function), “moderate improvement” (improvement in primary symptoms but not completely resolved; no impairments in daily function), and “marked improvement” (complete resolution of relapse symptoms). The lowest degree of improvement (between patient, Transfusion Medicine, and treating Neurologist assessments) was selected as the clinical response for each TPE series. RESULTS Patient Characteristics and Demographics
The clinical characteristics and demographics of the five patients are summarized (Table I). All patients
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TABLE I. Patient Characteristics of Five Patients Undergoing TPE for NMO
ID
Age (yr)
Gender/Race
Age of NMO onset (yr)
Duration of disease (yr)
1
28
F/Asian
13
15
2
65
F/Caucasian
58
7
3
45
M/Caucasian
42
3
4
39
F/African American
39
0
5
21
F/African American
19
2
Other associated autoimmune disease or autoantibody Sjogrens syndrome (SS-A and SS-B, ANA) Myasthenia gravisa None Myasthenia gravisa, SLE (dsDNA, ANA) ANA
Anti-AQP4 (NMO IgG)
Spinal cord involvement on MRI
1
C5-T8
MEP, AZP, RTX
1
C4-C7
2
T6-T8, T10-L1
1
T3-T4
MEP, AZP, RTX MEP, AZP, RTX,MYCO MEP, MYCO, PRED
1
C4-T1
Other treatments
MEP, AZP, RTX, PRED
TPE, therapeutic plasma exchange; NMO, neuromyelitis optica; yr, year; F, female; M, male; SLE, systemic lupus erythematosus; ANA, anti-nuclear antibody. Association with Anti-AQP4 (NMO IgG) is indicated by (1). Spinal cord lesion location is indicated by C, cervical; T, thoracic; and L, lumbar. Other treatments include those administered during clinical course MEP, methylprednisolone; AZP, azathioprine; RTX, rituximab; MYCO, mycophenolate; PRED, prednisone. a Diagnosis made at another institution; antibody testing not available.
met NMO criteria as proposed by Wingerchuk et al. [10]. Four of five patients had MRI evidence of acute myelitis with spinal cord lesions covering three or more continuous vertebral segments (ranged 3–9). The one patient that did not have spinal cord lesions covering three or more continuous vertebral segments was positive for NMO-IgG. All patients were tested for NMO-IgG and 80% (four of the five) patients were seropositive. The one patient that was seronegative for NMO-IgG had spinal cord lesions covering three or more continuous vertebral segments. Four of the five patients were female, two were Caucasian, two were African American, and one was Asian. The median age at NMO diagnosis was 34 years (ranged 13–58). Based on a definition of the duration of NMO disease as the age of the patient at the time of this review minus the age of the patient at time of NMO diagnosis, the median duration of NMO disease was 5.4 years (ranged 0–15). Four patients had an additional autoimmune disease (one with Sjogren’s syndrome and two with myasthenia gravis) or autoantibody [three with a positive anti-nuclear (ANA) titer, and one with a positive double-stranded DNA (dsDNA)]; the diagnosis of myasthenia gravis was made at another institution and antibody testing was not available (Table I). The one NMO-IgG seronegative patient did not have any other associated autoimmune diseases or autoantibody. All patients received acute corticosteroid pharmacotherapy (1–2 g methylprednisolone per day), yet continued to worsen prior to
the initiation of TPE. Concurrent corticosteroid pharmacotherapy was typically given for 5 days and repeated if there was continued worsening of symptoms. All patients were also treated with long-term pharmacotherapy, including azathioprine (4 patients), rituximab (4 patients), mycophenolate (2 patients), and prednisone (2 patients; Table I). Treatment of Acute Attacks with TPE
There were a total of 26 acute NMO exacerbations of which 17 TPE series were performed (Table II). The average TPE series consisted of five exchanges (ranged 3–7), and patients received a mean of three series (ranged 1–5) of TPE for NMO exacerbations. The mean time from the start of the acute attack to TPE for the first series was 10.0 days (ranged 4–20) and thereafter the mean time from acute attack to TPE was 3.8 days (ranged 2–9). Three patients did not start the first TPE until 10 or more days after the symptoms started. Patient ID#2 had an extensive medical history of presumed multiple sclerosis and diplopia and was being followed at a rural physician’s office with multiple rural hospital admissions for uncontrolled relapses. She was referred to our institution after being discharged for an exceptionally severe relapse of transverse myelitis, pain, urinary urgency, and intense fatigue not responding to steroids. She was seen in our outpatient neurology clinic and on the following day began a trial of TPE (10 days after onset of symptoms). Patient Journal of Clinical Apheresis DOI 10.1002/jca
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TABLE II.
TPE Treatment Protocol and Clinical Outcomes
ID
Number of acute attacks
TPE series number
1
8
1 2 3 4 1 2 3 4 mTPE
2
4
3
11
1 2 3 4 5 mTPE
4 5
1 3
1 1 2 3
TPE protocol
Days from onset of symptoms to TPE
Clinical improvement by TPE #
Overall clinical improvement
4 3
5 6
Mild Mild
6 2 10 4 3 5 NA
4 2 2 4 5 2 NA
Mild Mild Moderate Mild Moderate Mild Moderate
20 4 3 2 3 NA
4 2 3 4 3 NA
Moderate Moderate Moderate Moderate Marked Marked
4 12
3 3
Moderate Marked
9 3
5 2
Moderate Moderate
5 qod 7 total (3 qod, then 4 qd) 5 qod 3 qod 5 qod 4 qod 5 qod 3 qod 1 x per week, 6 total 5 qod 6 qod 5 qod 5 qod 5 qod 2 x per month, 10 total 5 qod 7 total (2 qd, then 5 qod) 5 qod 5 qod
TPE, therapeutic plasma exchange; mTPE, maintenance therapeutic plasma exchange; qod, every other day; qd, daily; NA, not applicable.
ID#3 was experiencing Lhermitte’s phenomenon and urinary retention. When these symptoms did not resolve after several days, he went to a community hospital emergency department and was thereafter admitted. During admission, he was misdiagnosed with shingles and possible Lyme disease and while there he developed pain behind the right eye and blurred vision which subsequently worsened to the point of seeing only a minimum amount of light. He was then transferred to our institution and a work-up of NMO was begun. TPE for suspected NMO began on hospital day 2 at our institution; this was day 20 after his symptoms began. Patient ID#5 had a long medical history of neurological processes of unknown etiology (thought to be related to systemic lupus erythematosus versus multiple sclerosis) that was admitted to a community hospital with transverse myelitis, double vision, fatigue, nausea, and vomiting. She had some interval resolution and was then transferred to our institution for rehabilitation placement. TPE for presumed NMO was begun on hospital day 6 of our institution (12 days after onset of symptoms). All patients demonstrated improvement with at least one series of TPE. There was marked improvement in 12% (2/17) of the TPE series, moderate improvement in 53% (9/17) TPE series, mild improvement in 35% (6/17) TPE series, and no improvement in 0% (0/17) TPE series. Improvement was seen on average by the third procedure (ranged 2–6) in the series (Table II). Journal of Clinical Apheresis DOI 10.1002/jca
Of note, patient ID#4 showed moderate to marked overall clinical improvement in all TPE series and a brain MRI was obtained pre- and post-series five which showed significantly decreased size of an area of T2 signal abnormality within the subcortical and deep white matter of the right frontal lobe. Patients ID#1 and #2 showed mild to moderate overall clinical improvement, while patients ID#3, #4, and #5 showed moderate to marked improvement with each series. The median disease duration was shorter in the latter (2 years versus 11 years). Preventative Treatment with Maintenance TPE (mTPE)
Patients who were resistant or intolerant to their pharmacotherapy, yet had responded to acute TPE, were considered for mTPE. Resistance to pharmacotherapy was defined as continued deterioration and more than one relapse while on multiple immunomodulating agents. Intolerance to pharmacotherapy was defined as having side effects that significantly interfered with activities of daily life. There were a total of 16 mTPE performed on two patients (ID#2 and #3). Patient ID#2 had a total of six mTPE on a schedule of once weekly. Patient ID#3 had a total of 10 mTPE on a schedule of twice monthly. Both patients had residual base-line deficits from previous attacks; patient ID#2 experienced moderate improvement and patient ID#3
TPE in NMO: A Case Series
experienced marked improvement early in the series of mTPE. Neither patient had an acute NMO relapse while on mTPE therapy. Patient ID#2 discontinued mTPE secondary to beginning an indefinite course of rituximab that was well-tolerated and clinically effective. Patient ID#3 discontinued mTPE due to issues with immunosuppression and infection risks associated with a tunneled catheter. Attempts to use peripheral IV access were unsuccessful and the patient declined to pursue a fistula. TPE Tolerability
A total of 101 TPE were performed, including mTPE. All procedures were well tolerated with only transient and well-described reactions all of which were successfully resolved with minor or no sequelae. Of the 101 procedures, 23 were associated with an adverse event (AE) for a rate of 23%. A total of 28 AEs occurred. These AEs include the following: 16% (16/101) line complications [5% pain, 4% mild bleeding at entry site, 3% line-reversal, 3% required treatment with tissue plasminogen activator (tPA), 1% infiltrated], 4% (4/101) numbness/tingling indicative of hypocalcemia related to ACD solution and managed with increasing of the dose of intravenous calcium infusion, 3% (3/101; two of three related to plasma usage) allergic, 2% (2/101) hypotension corrected by temporarily pausing the procedure and/or giving intravenous fluids, 2% (2/101) low platelets (111 3 109/L, 145 3 109/L), 1% (1/101) nausea, and 0% (0/101) cases of severe hypofibrinogenemia (as defined by a pre-procedural fibrinogen of less than 100 mg/dL). All patients required temporary non-tunneled intrajugular catheter placement prior to each TPE series secondary to inadequate peripheral access; patient ID#2 and #3 received long-term tunneled subclavian catheters prior to beginning mTPE. Plasma replacement was used in 3% (3/101) of procedures; twice for preventative coagulopathy pre- and post-kidney biopsy (patient ID#1) and once for elevated pre-procedural INR while patient was on warfarin (1/3 plasma and 2/3 5% albumin used per clinical and apheresis physician’s clinical judgment). One procedure was aborted early (on the last bottle of 5% albumin) secondary to an infiltrated line. DISCUSSION
Neuromyelitis optica (NMO) is a severe, often debilitating autoimmune neurologic disorder. This case series provides evidence that TPE might be an effective adjunct therapy in the management of steroidunresponsive acute attacks of NMO. All of the patients in this study demonstrated improvement with each TPE series. All patients were initially treated with corticosteroid pharmacotherapy with no relief of symptoms
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and improved after initiation of TPE, with signs of improvement seen on average by the third procedure. This study observed all patients demonstrated improvement with each series of TPE for an overall response rate of 100%. Among the 17 series of TPE, 79% (11 of 17) had a significant improvement, as defined as a moderate or marked improvement. This rate is similar to previous studies which reported an overall response rate of 50–89% in patients receiving TPE [14,15,17,20,21,25–28]. Mild improvement was seen in 35% (6 of 17) series of TPE. When the mild improvement responders were included in other studies, the response rate increased to 70–100% [14,25,28]. Compiling our data with other series that reported data by patient receiving TPE, a significant response was seen in 67% (82 of 123) patients [14,15,17,20,21,25,27,28]. While the data does not lend itself to statistical analysis, the three patients with shorter duration of disease had a more marked response to TPE (Tables I and II). This has also been noted previously by Magana et al [15]. Immunosuppressive medications and immunomodulation have shown to be effective for prevention of attacks; however, few data exists on treatment of acute attacks [4,29–31]. Acute attacks are systematically managed by high-dose corticosteroids as they have been shown to accelerate recovery; however, there are various dosing regimens in place and an assessment of their efficacy has not been documented [8]. Furthermore, there are no randomized controlled trials (RCT) of TPE in addition to steroids versus steroids alone, but it is clear that steroid treatment alone is not always sufficient in that morbidity continues to be a frequent issue despite immediate steroid treatment [8]. The time to initiation of TPE has been associated with the response rate [15,25]. In this study, the time from symptoms to first TPE in a series averaged 10.0 days for the first series and 3.8 for subsequent series which was short compared to some algorithms reported in the literature [8,15]. At our institution, high-dose corticosteroids are typically started immediately when an NMO relapse is diagnosed, and TPE is offered for NMO attacks that do not respond to steroids within several days, or for patients who have shown a prior positive response to TPE. Early initiation of TPE has been associated with improved outcome in some studies [21,25], but not all [15]. This discordance may be due to the large time frames (>20 days) used for the analysis. A lower level of baseline disability is associated with a favorable TPE response [8,27]. We did not determine the expanded disability status scale (EDSS) on our subjects; however aspects of the EDSS was incorporated into our review of the patients’ improvement and all patients demonstrated an objective or subjective improvement which would translate to a lowered EDSS score post-TPE. While NMO-IgG is used for the diagnosis of the disorder, the presence of Journal of Clinical Apheresis DOI 10.1002/jca
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this antibody has not been associated with response to TPE [15,16,27]. In our study, the one seronegative subject (patient ID#3), had a moderate to marked response with all five series of TPE. The patients who receive TPE in our study and other studies may have a selection bias. In our institution, the selection of who receives TPE versus staying on conventional therapies is left up to the treating provider. Bonnan et al. [16] compared the response of all subjects with NMO and extensive transverse myelitis treated with conventional therapy of corticosteroids versus those treated with corticosteroids and TPE. This study found the change in EDSS from basal to residual EDSS was better in the TPE treated group (1.2 6 1.6 versus 2.6 6 2.3, P < 0.01). Two of our subjects were started on a maintenance protocol of TPE (mTPE). This reduced their relapse rate to zero during the time-frame that they were receiving mTPE. MTPE might offer preventative intervention as evidenced by the decrease in the number of acute attacks in our patients and in the literature, as well [22,23]. MTPE is a relatively new concept. Only nine patients have been reported in the literature and only two of these patients complied with this therapy for a duration greater than 10 years [22,23]. Therefore, the data is scant on long-term feasibility and effectiveness. Furthermore, although there are protocols and algorithms suggested by case reports and small case series, there is no consensus on the frequency of mTPE to offer clinicians interested in this application for their patients. Future studies in prophylactic therapies would ideally clarify both the role of mTPE and immunomodulating medications. TPE is a relatively safe and well tolerated procedure. Our study had a total of 28 AEs over 23 procedures giving an overall AE rate of 23% (23/101) per procedure. This rate is higher than published in previous studies (ranged 4.6–17%); however, this study captured all reported patient complaints, including some AEs not captured by other studies, such as line pain and minor difficulties with flow through the catheter [32–36]. All AEs in were minor and successfully resolved with minor or no sequelae. They included line-related issues, hypocalcemia, allergic, low platelets, and hypotension. Line related issues were the most common AEs, which suggests if one can avoid line placement, the overall percentage of AEs might decrease. Furthermore, understanding the physiological changes that occur during apheresis and knowledge of underlying medical conditions in the patient that would predispose them toward these reactions would allow for early intervention and potentially lessoning the severity of these reactions. This study is limited in that it is a retrospective case review. There have been several published retrospective studies which have shown a favorable response, Journal of Clinical Apheresis DOI 10.1002/jca
and no RCTs on TPE in the setting of acute neurological decompensation secondary to NMO [16,17]. Ideally, there would be an RCT to determine whether patients with NMO in an acute crisis improve faster when TPE is initiated on day one in addition to steroids versus steroids alone. There are a number of challenges to performing such a trial. The timing of initiating TPE may be critical and as we have seen in our study there are many reasons that TPE is delayed (issues with access, outside institution, etc.). Some relapses are mild and may not warrant TPE and so some type of severity entry criteria would be needed. NMO is a rare disease; however, with new diagnostic technologies and increasing clinical awareness, we may see a feasible increase of these patients in the future. To support this, recently three tertiary centers (Johns Hopkins University, Mayo Clinic, and University of Texas Southwestern) were able to recruit 187 NMO patients within a 5-year timeframe [7]. CONCLUSIONS
This case series suggests that acute attacks of NMO are safely and effectively treated with TPE, with clinical improvement most often appearing by the third TPE of a series. The study also suggests that mTPE may be effective in reducing the number of acute NMO attacks. Further studies are needed to examine which clinical characteristics may predict a better response to TPE and whether this treatment should be used for all patients with NMO and earlier in the onset of an acute attack. RCTs are needed to further establish the benefit of TPE in NMO, particularly in a time period where neurological diseases appear to be on the rise and apheresis physicians are more often being requested upon to perform TPE and offer evidence of its effectiveness [37]. REFERENCES 1. Wingerchuk DM. Neuromyelitis optica. Int MS J 2006;13: 42–50. 2. Lucchinetti CF, Mandler RN, McGavern D, Bruck W, Gleich G, Ransohoff RM, Trebst C, Weinshenker B, Wingerchuk D, Parisi JE, Lassmann H. A role for humoral mechanisms in the pathogenesis of Devic’s neuromyelitis optica. Brain 2002;125: 1450–1461. 3. Wingerchuk DM, Hogancamp WF, O’Brien PC, Weinshenker BG. The clinical course of neuromyelitis optica (Devic’s syndrome). Neurology 1999;53:1107–1114. 4. Argyriou AA, Makris N. Neuromyelitis optica: a distinct demyelinating disease of the central nervous system. Acta Neurol Scand 2008;118:209–217. 5. Weinshenker BG, Wingerchuk DM, Vukusic S, Linbo L, Pittock SJ, Lucchinetti CF, Lennon VA. Neuromyelitis optica IgG predicts relapse after longitudinally extensive transverse myelitis. Ann Neurol 2006;59:566–569. 6. Weinshenker BG, Wingerchuk DM, Pittock SJ, Lucchinetti CF, Lennon VA. NMO-IgG: a specific biomarker for neuromyelitis optica. Dis Markers 2006;22:197–206.
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22. Khatri BO, Kramer J, Dukic M, Palencia M, Verre W. Maintenance plasma exchange therapy for steroid-refractory neuromyelitis optica. J Clin Apher 2012;27:183–192. 23. Miyamoto K, Kusunoki S. Intermittent plasmapheresis prevents recurrence in neuromyelitis optica. Ther Apher Dial 2009;13: 505–508. 24. Lehmann HC, Hartung HP, Hetzel GR, Stuve O, Kieseier BC. Plasma exchange in neuroimmunological disorders: Part 1: rationale and treatment of inflammatory central nervous system disorders. Arch Neurol 2006;63:930–935. 25. Keegan M, Pineda AA, McClelland RL, Darby CH, Rodriguez M, Weinshenker BG. Plasma exchange for severe attacks of CNS demyelination: predictors of response. Neurology 2002;58:143–146. 26. Kim SH, Kim W, Huh SY, Lee KY, Jung IJ, Kim HJ. Clinical efficacy of plasmapheresis in patients with neuromyelitis optica spectrum disorder and effects on circulating anti-aquaporin-4 antibody levels. J Clin Neurol 2013;9:36–42. 27. Lim YM, Pyun SY, Kang BH, Kim J, Kim KK. Factors associated with the effectiveness of plasma exchange for the treatment of NMO-IgG-positive neuromyelitis optica spectrum disorders. Mult Scler 2013;19:1216–1218. 28. Munemoto M, Otaki Y, Kasama S, Nanami M, Tokuyama M, Yahiro M, Hasuike Y, Kuragano T, Yoshikawa H, Nonoguchi H, Nakanishi T. Therapeutic efficacy of double filtration plasmapheresis in patients with anti-aquaporin-4 antibody-positive multiple sclerosis. J Clin Neurosci 2011;18:478–480. 29. Bakker J, Metz L. Devic’s neuromyelitis optica treated with intravenous gamma globulin (IVIG). Can J Neurol Sci 2004;31: 265–267. 30. Mandler RN, Ahmed W, Dencoff JE. Devic’s neuromyelitis optica: a prospective study of seven patients treated with prednisone and azathioprine. Neurology 1998;51:1219–1220. 31. Wingerchuk DM. Diagnosis and treatment of neuromyelitis optica. Neurologist 2007;13:2–11. 32. Couriel D, Weinstein R. Complications of therapeutic plasma exchange: a recent assessment. J Clin Apher 1994;9:1–5. 33. Norda R, Berseus O, Stegmayr B. Adverse events and problems in therapeutic hemapheresis. A report from the Swedish registry. Transfus Apher Sci 2001;25:33–41. 34. McLeod BC, Sniecinski I, Ciavarella D, Owen H, Price TH, Randels MJ, Smith JW. Frequency of immediate adverse effects associated with therapeutic apheresis. Transfusion 1999;39:282–288. 35. Korach JM, Guillevin L, Petitpas D, Berger P, Chillet P. Apheresis registry in France: indications, techniques, and complications. French Registry Study Group. Ther Apher 2000;4:207–210. 36. Rodnitzky RL, Goeken JA. Complications of plasma exchange in neurological patients. Arch Neurol 1982;39:350–354. 37. Clark WF, Rock GA, Buskard N, Shumak KH, LeBlond P, Anderson D, Sutton DM. Therapeutic plasma exchange: an update from the Canadian Apheresis Group. Ann Intern Med 1999;131:453–462.
Journal of Clinical Apheresis DOI 10.1002/jca
Case Report Therapeutic Plasma Exchange in Neuromyelitis Optica: A Case Series Shanna M. Morgan,1* Nicole D. Zantek,1 and Adam F. Carpenter2 1
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 2 Department of Neurology, University of Minnesota, Minneapolis, Minnesota Neuromyelitis optica (NMO) is a relapsing inflammatory disease of the central nervous system that predominantly affects the spinal cord and optic nerves. The clinical hallmark of the disease is a step-wise deterioration of visual and spinal cord function. This study reviews patients with steroid resistant relapsing NMO presenting for therapeutic plasma exchange (TPE) at our institution from December 2005 to December 2012. A total of five patients were treated with single volume TPE. Both subjective and objective clinical response to TPE was estimated by three different sources (the patient, a Transfusion Medicine physician, and the treating Neurologist) with the patient and Transfusion Medicine physician’s final assessment of response made at the time of the last TPE in the series and the treating neurologist’s assessment of response made at the time of the next neurological exam after the last TPE. A total of 17 TPE series were performed with the average course of therapy being three series (ranged 1–5) with five TPE (ranged 3–7) per series. All patients demonstrated improvement with each series of TPE and all procedures were well tolerated with only transient and well-described reactions all of C 2013 which were successfully resolved with minor or no sequelae. J. Clin. Apheresis 29:171–177, 2014. V Wiley Periodicals, Inc.
Key words: apheresis; Devic’s disease; optic neuritis
INTRODUCTION
Neuromyelitis optica (NMO) is a severe inflammatory disease that typically affects the spinal cord and optic nerves, while sparing the brain [1]. The clinical hallmark of the disease is a relapsing-remitting course of optic neuritis and myelitis resulting in a step-wise deterioration of visual and neurologic function [2]. Clinical features are diverse and may include the following: unilateral or bilateral visual field deficits, ocular pain, severe paraplegia, sensory loss below the lesion, bowel and bladder dysfunction, paroxysmal tonic spasms of the trunk and limbs, intractable hiccups, nausea, and Lhermitte’s phenomenon [3–5]. Historically, NMO has been considered a rare disease; however, this is likely due to under-diagnosis, mostly commonly from a misdiagnosis of multiple sclerosis (MS) [6]. NMO prevalence in the United States is estimated to be approximately 4,000 to 8,000 patients [7]. Diagnostic frequency and accuracy has undoubtedly increased since the recent development of anti-aquaporin 4 antibody (NMO-IgG) as a serologic marker of NMO. Aquaporin 4 (AQP-4) is a protein expressed on the astrocyte foot processes that is involved in water homeostasis throughout the central nervous system [4,8,9]. Immunopathological studies C 2013 Wiley Periodicals, Inc. V
indicate NMO to be an acute antibody-mediated inflammatory process involving AQP-4 [4]. Loss of AQP-4 leads to edema, axonal injury, demyelination, necrosis, and cavitation [8,9]. Serologic testing for NMO-IgG can aid in the diagnosis and is incorporated into the diagnostic criteria put forth by Wingerchuk et al. [10]. The diagnostic criteria state that a patient must have (1) optic neuritis, (2) acute myelitis, and (3) at least two of the three following elements: (a) MRI showing contiguous spinal cord lesions extending three or more vertebral segments, (b) non-diagnostic brain MRI for multiple sclerosis, or (c) NMO-IgG seropositive status [10]. NMO-IgG seropositivity is reported to have a sensitivity of 76% and a specificity of 94% and is a strong predictor of a relapsing course [8,10]. Evidence suggests that there are two major clinical courses of NMO, monophasic and relapsing [11]. The *Correspondence to: Shanna M. Morgan, Department of Laboratory Medicine and Pathology, Division of Transfusion Medicine, D242 Mayo Building, MMC 609, 420 Delaware Street S.E., Minneapolis, MN 55455. E-mail: [email protected] Received 3 May 2013; Accepted 20 September 2013 Published online 17 October 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jca.21304
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monophasic form presents as a bilateral optic neuritis and transverse myelitis storm, as they occur simultaneously or within days of each other. Although the short term prognosis is worse in patients with monophasic NMO, the long-term prognosis is better because these patients typically do not have recurrent attacks leading to further disabilities [1]. Monophasic NMO patients are younger individuals, with an equal sex ratio, and overall they have a lower percentage of NMO-IgG positivity as compared to the relapsing group [1,12]. Relapsing NMO is by far more common, accounting for 80% or more of cases [1,4,6]. These patients typically present in the fourth or fifth decade, have a strong predilection for females at a ratio of approximately 7:1, and have an overall higher percentage of NMO-IgG positivity [6,7]. These patients have a rather unpredictable clinical course with recurrent attacks of optic myelitis and transverse myelitis at intervals of months to years [11]. Severe cervical myelitis with possible respiratory failure and death is a major health concern in relapsing NMO, comprising the majority of the 20% of patients who die within the first 5 years [3,11,13]. Once a diagnosis of NMO is made, the therapeutic goals for these patients include quickly preventing further production of the offending antibody with immunosuppressive therapy. In patients who do not respond to pharmacotherapy, therapeutic plasma exchange (TPE) may be beneficial in both the acute setting and in the preventative setting [8,14–23]. The benefits are likely through removal of circulating pathogenic immune or inflammatory substances [24]. We present a retrospective study of five patients with relapsing NMO who were treated with TPE as acute immunotherapy for NMO relapses. In addition, two of these patients were treated with additional maintenance TPE (mTPE) in between attacks as preventative therapy. MATERIALS AND METHODS Patients
A retrospective review was performed on patients with steroid resistant relapsing NMO presenting for TPE at our institution from December 2005 to December 2012. Informed, written consent to use the patient’s medical record for research was obtained at time of first TPE and this study was approved by our institutional review board. The five patients reviewed in this study were diagnosed with NMO based on criteria proposed by Wingerchuk et al. in 2006 [10]. Additional inclusion criteria for this study required that the patient be experiencing an acute or subacute worsening of neurological symptoms for greater than 24 h, without evidence of new infection or other underlying acute medical condition, and deemed by a neurologist to be an acute NMO attack. Journal of Clinical Apheresis DOI 10.1002/jca
NMO-IgG Serology
NMO-IgG serologies were tested at the Mayo Medical Laboratories, Mayo Clinic, Rochester, MN. TPE and mTPE Protocol R
Single volume TPE were performed with a CobeV Spectra cell separator (TerumoBCT, Lakewood, CO) using 5% albumin for replacement fluid. Anticoagulant Citrate Dextrose Solution A (ACD-A) was used for extracorporeal anticoagulation at an anticoagulant to whole blood ratio of 1:13. Prophylactic intravenous 10% calcium gluconate infusion was given through the return line over the duration of the procedure to offset the effects of the citrate-based anticoagulant. The rate of calcium gluconate solution infusion ranged from 800 mg/L for 5% albumin replacement or 1,000 mg/L for plasma replacement with the rate increased up to a maximum of 2,400 and 3,000 mg/L, respectively, in the presence of citrate toxicity symptoms (paresthesia, tingling, muscle cramps, nausea) or ionized calcium levels below the reference range. Clinical Assessments
We evaluated the effect of TPE on the degree of recovery from NMO relapse as follows. The time of onset and primary symptom(s) of the relapse were identified from the treating neurologists hospital or clinic notes. Both subjective and objective clinical response to TPE was estimated by three different sources (the patient, a Transfusion Medicine physician, and the treating Neurologist). With each TPE, an apheresis nurse and physician evaluated each patient. The patient and Transfusion Medicine physician’s final assessment of response was made at the time of the last TPE in the series. The treating neurologist’s assessment of response was made at the time of the next neurological exam after the last TPE. Response was estimated as degree of improvement in the primary relapse symptoms, similar to Keegan et al 2002 [25]: “no improvement” (no improvement in neurological symptoms or function), “mild improvement” (improvement in symptoms or exam, but with residual impairments in daily function), “moderate improvement” (improvement in primary symptoms but not completely resolved; no impairments in daily function), and “marked improvement” (complete resolution of relapse symptoms). The lowest degree of improvement (between patient, Transfusion Medicine, and treating Neurologist assessments) was selected as the clinical response for each TPE series. RESULTS Patient Characteristics and Demographics
The clinical characteristics and demographics of the five patients are summarized (Table I). All patients
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TABLE I. Patient Characteristics of Five Patients Undergoing TPE for NMO
ID
Age (yr)
Gender/Race
Age of NMO onset (yr)
Duration of disease (yr)
1
28
F/Asian
13
15
2
65
F/Caucasian
58
7
3
45
M/Caucasian
42
3
4
39
F/African American
39
0
5
21
F/African American
19
2
Other associated autoimmune disease or autoantibody Sjogrens syndrome (SS-A and SS-B, ANA) Myasthenia gravisa None Myasthenia gravisa, SLE (dsDNA, ANA) ANA
Anti-AQP4 (NMO IgG)
Spinal cord involvement on MRI
1
C5-T8
MEP, AZP, RTX
1
C4-C7
2
T6-T8, T10-L1
1
T3-T4
MEP, AZP, RTX MEP, AZP, RTX,MYCO MEP, MYCO, PRED
1
C4-T1
Other treatments
MEP, AZP, RTX, PRED
TPE, therapeutic plasma exchange; NMO, neuromyelitis optica; yr, year; F, female; M, male; SLE, systemic lupus erythematosus; ANA, anti-nuclear antibody. Association with Anti-AQP4 (NMO IgG) is indicated by (1). Spinal cord lesion location is indicated by C, cervical; T, thoracic; and L, lumbar. Other treatments include those administered during clinical course MEP, methylprednisolone; AZP, azathioprine; RTX, rituximab; MYCO, mycophenolate; PRED, prednisone. a Diagnosis made at another institution; antibody testing not available.
met NMO criteria as proposed by Wingerchuk et al. [10]. Four of five patients had MRI evidence of acute myelitis with spinal cord lesions covering three or more continuous vertebral segments (ranged 3–9). The one patient that did not have spinal cord lesions covering three or more continuous vertebral segments was positive for NMO-IgG. All patients were tested for NMO-IgG and 80% (four of the five) patients were seropositive. The one patient that was seronegative for NMO-IgG had spinal cord lesions covering three or more continuous vertebral segments. Four of the five patients were female, two were Caucasian, two were African American, and one was Asian. The median age at NMO diagnosis was 34 years (ranged 13–58). Based on a definition of the duration of NMO disease as the age of the patient at the time of this review minus the age of the patient at time of NMO diagnosis, the median duration of NMO disease was 5.4 years (ranged 0–15). Four patients had an additional autoimmune disease (one with Sjogren’s syndrome and two with myasthenia gravis) or autoantibody [three with a positive anti-nuclear (ANA) titer, and one with a positive double-stranded DNA (dsDNA)]; the diagnosis of myasthenia gravis was made at another institution and antibody testing was not available (Table I). The one NMO-IgG seronegative patient did not have any other associated autoimmune diseases or autoantibody. All patients received acute corticosteroid pharmacotherapy (1–2 g methylprednisolone per day), yet continued to worsen prior to
the initiation of TPE. Concurrent corticosteroid pharmacotherapy was typically given for 5 days and repeated if there was continued worsening of symptoms. All patients were also treated with long-term pharmacotherapy, including azathioprine (4 patients), rituximab (4 patients), mycophenolate (2 patients), and prednisone (2 patients; Table I). Treatment of Acute Attacks with TPE
There were a total of 26 acute NMO exacerbations of which 17 TPE series were performed (Table II). The average TPE series consisted of five exchanges (ranged 3–7), and patients received a mean of three series (ranged 1–5) of TPE for NMO exacerbations. The mean time from the start of the acute attack to TPE for the first series was 10.0 days (ranged 4–20) and thereafter the mean time from acute attack to TPE was 3.8 days (ranged 2–9). Three patients did not start the first TPE until 10 or more days after the symptoms started. Patient ID#2 had an extensive medical history of presumed multiple sclerosis and diplopia and was being followed at a rural physician’s office with multiple rural hospital admissions for uncontrolled relapses. She was referred to our institution after being discharged for an exceptionally severe relapse of transverse myelitis, pain, urinary urgency, and intense fatigue not responding to steroids. She was seen in our outpatient neurology clinic and on the following day began a trial of TPE (10 days after onset of symptoms). Patient Journal of Clinical Apheresis DOI 10.1002/jca
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TABLE II.
TPE Treatment Protocol and Clinical Outcomes
ID
Number of acute attacks
TPE series number
1
8
1 2 3 4 1 2 3 4 mTPE
2
4
3
11
1 2 3 4 5 mTPE
4 5
1 3
1 1 2 3
TPE protocol
Days from onset of symptoms to TPE
Clinical improvement by TPE #
Overall clinical improvement
4 3
5 6
Mild Mild
6 2 10 4 3 5 NA
4 2 2 4 5 2 NA
Mild Mild Moderate Mild Moderate Mild Moderate
20 4 3 2 3 NA
4 2 3 4 3 NA
Moderate Moderate Moderate Moderate Marked Marked
4 12
3 3
Moderate Marked
9 3
5 2
Moderate Moderate
5 qod 7 total (3 qod, then 4 qd) 5 qod 3 qod 5 qod 4 qod 5 qod 3 qod 1 x per week, 6 total 5 qod 6 qod 5 qod 5 qod 5 qod 2 x per month, 10 total 5 qod 7 total (2 qd, then 5 qod) 5 qod 5 qod
TPE, therapeutic plasma exchange; mTPE, maintenance therapeutic plasma exchange; qod, every other day; qd, daily; NA, not applicable.
ID#3 was experiencing Lhermitte’s phenomenon and urinary retention. When these symptoms did not resolve after several days, he went to a community hospital emergency department and was thereafter admitted. During admission, he was misdiagnosed with shingles and possible Lyme disease and while there he developed pain behind the right eye and blurred vision which subsequently worsened to the point of seeing only a minimum amount of light. He was then transferred to our institution and a work-up of NMO was begun. TPE for suspected NMO began on hospital day 2 at our institution; this was day 20 after his symptoms began. Patient ID#5 had a long medical history of neurological processes of unknown etiology (thought to be related to systemic lupus erythematosus versus multiple sclerosis) that was admitted to a community hospital with transverse myelitis, double vision, fatigue, nausea, and vomiting. She had some interval resolution and was then transferred to our institution for rehabilitation placement. TPE for presumed NMO was begun on hospital day 6 of our institution (12 days after onset of symptoms). All patients demonstrated improvement with at least one series of TPE. There was marked improvement in 12% (2/17) of the TPE series, moderate improvement in 53% (9/17) TPE series, mild improvement in 35% (6/17) TPE series, and no improvement in 0% (0/17) TPE series. Improvement was seen on average by the third procedure (ranged 2–6) in the series (Table II). Journal of Clinical Apheresis DOI 10.1002/jca
Of note, patient ID#4 showed moderate to marked overall clinical improvement in all TPE series and a brain MRI was obtained pre- and post-series five which showed significantly decreased size of an area of T2 signal abnormality within the subcortical and deep white matter of the right frontal lobe. Patients ID#1 and #2 showed mild to moderate overall clinical improvement, while patients ID#3, #4, and #5 showed moderate to marked improvement with each series. The median disease duration was shorter in the latter (2 years versus 11 years). Preventative Treatment with Maintenance TPE (mTPE)
Patients who were resistant or intolerant to their pharmacotherapy, yet had responded to acute TPE, were considered for mTPE. Resistance to pharmacotherapy was defined as continued deterioration and more than one relapse while on multiple immunomodulating agents. Intolerance to pharmacotherapy was defined as having side effects that significantly interfered with activities of daily life. There were a total of 16 mTPE performed on two patients (ID#2 and #3). Patient ID#2 had a total of six mTPE on a schedule of once weekly. Patient ID#3 had a total of 10 mTPE on a schedule of twice monthly. Both patients had residual base-line deficits from previous attacks; patient ID#2 experienced moderate improvement and patient ID#3
TPE in NMO: A Case Series
experienced marked improvement early in the series of mTPE. Neither patient had an acute NMO relapse while on mTPE therapy. Patient ID#2 discontinued mTPE secondary to beginning an indefinite course of rituximab that was well-tolerated and clinically effective. Patient ID#3 discontinued mTPE due to issues with immunosuppression and infection risks associated with a tunneled catheter. Attempts to use peripheral IV access were unsuccessful and the patient declined to pursue a fistula. TPE Tolerability
A total of 101 TPE were performed, including mTPE. All procedures were well tolerated with only transient and well-described reactions all of which were successfully resolved with minor or no sequelae. Of the 101 procedures, 23 were associated with an adverse event (AE) for a rate of 23%. A total of 28 AEs occurred. These AEs include the following: 16% (16/101) line complications [5% pain, 4% mild bleeding at entry site, 3% line-reversal, 3% required treatment with tissue plasminogen activator (tPA), 1% infiltrated], 4% (4/101) numbness/tingling indicative of hypocalcemia related to ACD solution and managed with increasing of the dose of intravenous calcium infusion, 3% (3/101; two of three related to plasma usage) allergic, 2% (2/101) hypotension corrected by temporarily pausing the procedure and/or giving intravenous fluids, 2% (2/101) low platelets (111 3 109/L, 145 3 109/L), 1% (1/101) nausea, and 0% (0/101) cases of severe hypofibrinogenemia (as defined by a pre-procedural fibrinogen of less than 100 mg/dL). All patients required temporary non-tunneled intrajugular catheter placement prior to each TPE series secondary to inadequate peripheral access; patient ID#2 and #3 received long-term tunneled subclavian catheters prior to beginning mTPE. Plasma replacement was used in 3% (3/101) of procedures; twice for preventative coagulopathy pre- and post-kidney biopsy (patient ID#1) and once for elevated pre-procedural INR while patient was on warfarin (1/3 plasma and 2/3 5% albumin used per clinical and apheresis physician’s clinical judgment). One procedure was aborted early (on the last bottle of 5% albumin) secondary to an infiltrated line. DISCUSSION
Neuromyelitis optica (NMO) is a severe, often debilitating autoimmune neurologic disorder. This case series provides evidence that TPE might be an effective adjunct therapy in the management of steroidunresponsive acute attacks of NMO. All of the patients in this study demonstrated improvement with each TPE series. All patients were initially treated with corticosteroid pharmacotherapy with no relief of symptoms
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and improved after initiation of TPE, with signs of improvement seen on average by the third procedure. This study observed all patients demonstrated improvement with each series of TPE for an overall response rate of 100%. Among the 17 series of TPE, 79% (11 of 17) had a significant improvement, as defined as a moderate or marked improvement. This rate is similar to previous studies which reported an overall response rate of 50–89% in patients receiving TPE [14,15,17,20,21,25–28]. Mild improvement was seen in 35% (6 of 17) series of TPE. When the mild improvement responders were included in other studies, the response rate increased to 70–100% [14,25,28]. Compiling our data with other series that reported data by patient receiving TPE, a significant response was seen in 67% (82 of 123) patients [14,15,17,20,21,25,27,28]. While the data does not lend itself to statistical analysis, the three patients with shorter duration of disease had a more marked response to TPE (Tables I and II). This has also been noted previously by Magana et al [15]. Immunosuppressive medications and immunomodulation have shown to be effective for prevention of attacks; however, few data exists on treatment of acute attacks [4,29–31]. Acute attacks are systematically managed by high-dose corticosteroids as they have been shown to accelerate recovery; however, there are various dosing regimens in place and an assessment of their efficacy has not been documented [8]. Furthermore, there are no randomized controlled trials (RCT) of TPE in addition to steroids versus steroids alone, but it is clear that steroid treatment alone is not always sufficient in that morbidity continues to be a frequent issue despite immediate steroid treatment [8]. The time to initiation of TPE has been associated with the response rate [15,25]. In this study, the time from symptoms to first TPE in a series averaged 10.0 days for the first series and 3.8 for subsequent series which was short compared to some algorithms reported in the literature [8,15]. At our institution, high-dose corticosteroids are typically started immediately when an NMO relapse is diagnosed, and TPE is offered for NMO attacks that do not respond to steroids within several days, or for patients who have shown a prior positive response to TPE. Early initiation of TPE has been associated with improved outcome in some studies [21,25], but not all [15]. This discordance may be due to the large time frames (>20 days) used for the analysis. A lower level of baseline disability is associated with a favorable TPE response [8,27]. We did not determine the expanded disability status scale (EDSS) on our subjects; however aspects of the EDSS was incorporated into our review of the patients’ improvement and all patients demonstrated an objective or subjective improvement which would translate to a lowered EDSS score post-TPE. While NMO-IgG is used for the diagnosis of the disorder, the presence of Journal of Clinical Apheresis DOI 10.1002/jca
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this antibody has not been associated with response to TPE [15,16,27]. In our study, the one seronegative subject (patient ID#3), had a moderate to marked response with all five series of TPE. The patients who receive TPE in our study and other studies may have a selection bias. In our institution, the selection of who receives TPE versus staying on conventional therapies is left up to the treating provider. Bonnan et al. [16] compared the response of all subjects with NMO and extensive transverse myelitis treated with conventional therapy of corticosteroids versus those treated with corticosteroids and TPE. This study found the change in EDSS from basal to residual EDSS was better in the TPE treated group (1.2 6 1.6 versus 2.6 6 2.3, P < 0.01). Two of our subjects were started on a maintenance protocol of TPE (mTPE). This reduced their relapse rate to zero during the time-frame that they were receiving mTPE. MTPE might offer preventative intervention as evidenced by the decrease in the number of acute attacks in our patients and in the literature, as well [22,23]. MTPE is a relatively new concept. Only nine patients have been reported in the literature and only two of these patients complied with this therapy for a duration greater than 10 years [22,23]. Therefore, the data is scant on long-term feasibility and effectiveness. Furthermore, although there are protocols and algorithms suggested by case reports and small case series, there is no consensus on the frequency of mTPE to offer clinicians interested in this application for their patients. Future studies in prophylactic therapies would ideally clarify both the role of mTPE and immunomodulating medications. TPE is a relatively safe and well tolerated procedure. Our study had a total of 28 AEs over 23 procedures giving an overall AE rate of 23% (23/101) per procedure. This rate is higher than published in previous studies (ranged 4.6–17%); however, this study captured all reported patient complaints, including some AEs not captured by other studies, such as line pain and minor difficulties with flow through the catheter [32–36]. All AEs in were minor and successfully resolved with minor or no sequelae. They included line-related issues, hypocalcemia, allergic, low platelets, and hypotension. Line related issues were the most common AEs, which suggests if one can avoid line placement, the overall percentage of AEs might decrease. Furthermore, understanding the physiological changes that occur during apheresis and knowledge of underlying medical conditions in the patient that would predispose them toward these reactions would allow for early intervention and potentially lessoning the severity of these reactions. This study is limited in that it is a retrospective case review. There have been several published retrospective studies which have shown a favorable response, Journal of Clinical Apheresis DOI 10.1002/jca
and no RCTs on TPE in the setting of acute neurological decompensation secondary to NMO [16,17]. Ideally, there would be an RCT to determine whether patients with NMO in an acute crisis improve faster when TPE is initiated on day one in addition to steroids versus steroids alone. There are a number of challenges to performing such a trial. The timing of initiating TPE may be critical and as we have seen in our study there are many reasons that TPE is delayed (issues with access, outside institution, etc.). Some relapses are mild and may not warrant TPE and so some type of severity entry criteria would be needed. NMO is a rare disease; however, with new diagnostic technologies and increasing clinical awareness, we may see a feasible increase of these patients in the future. To support this, recently three tertiary centers (Johns Hopkins University, Mayo Clinic, and University of Texas Southwestern) were able to recruit 187 NMO patients within a 5-year timeframe [7]. CONCLUSIONS
This case series suggests that acute attacks of NMO are safely and effectively treated with TPE, with clinical improvement most often appearing by the third TPE of a series. The study also suggests that mTPE may be effective in reducing the number of acute NMO attacks. Further studies are needed to examine which clinical characteristics may predict a better response to TPE and whether this treatment should be used for all patients with NMO and earlier in the onset of an acute attack. RCTs are needed to further establish the benefit of TPE in NMO, particularly in a time period where neurological diseases appear to be on the rise and apheresis physicians are more often being requested upon to perform TPE and offer evidence of its effectiveness [37]. REFERENCES 1. Wingerchuk DM. Neuromyelitis optica. Int MS J 2006;13: 42–50. 2. Lucchinetti CF, Mandler RN, McGavern D, Bruck W, Gleich G, Ransohoff RM, Trebst C, Weinshenker B, Wingerchuk D, Parisi JE, Lassmann H. A role for humoral mechanisms in the pathogenesis of Devic’s neuromyelitis optica. Brain 2002;125: 1450–1461. 3. Wingerchuk DM, Hogancamp WF, O’Brien PC, Weinshenker BG. The clinical course of neuromyelitis optica (Devic’s syndrome). Neurology 1999;53:1107–1114. 4. Argyriou AA, Makris N. Neuromyelitis optica: a distinct demyelinating disease of the central nervous system. Acta Neurol Scand 2008;118:209–217. 5. Weinshenker BG, Wingerchuk DM, Vukusic S, Linbo L, Pittock SJ, Lucchinetti CF, Lennon VA. Neuromyelitis optica IgG predicts relapse after longitudinally extensive transverse myelitis. Ann Neurol 2006;59:566–569. 6. Weinshenker BG, Wingerchuk DM, Pittock SJ, Lucchinetti CF, Lennon VA. NMO-IgG: a specific biomarker for neuromyelitis optica. Dis Markers 2006;22:197–206.
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Journal of Clinical Apheresis DOI 10.1002/jca
