Journal of Clinical Apheresis 31:63–65 (2016)
Case Report Therapeutic Plasma Exchange as a Steroid-Sparing Therapy in a Patient with Limbic Encephalitis Due to Antibodies to Voltage-Gated Potassium Channels Isabella W. Martin,1* Christi-Lynn B. Martin,1 Nancy M. Dunbar,1 Stephen L. Lee,2 and Zbigniew M. Szczepiorkowski1 1 2
Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire Department of Neurology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
Autoantibodies to the voltage-gated potassium channel (VGKC) complex cause a spectrum of non-paraneoplastic neurologic syndromes including limbic encephalitis (LE). We report a case of a man with LE who underwent a course of therapeutic plasma exchange (TPE) in addition to other immunomodulatory therapies and experienced sustained clinical resolution of his symptoms. This report adds to the existing literature supporting TPE in cases C 2015 Wiley Periodicals, Inc. of LE due to VGKC complex autoantibodies. J. Clin. Apheresis 31:63–65, 2016. V Key words: TPE; VGKC antibodies; LGI1antibodies
INTRODUCTION
Limbic encephalitis (LE) is one of several autoimmune, non-paraneoplastic, and variably treatable neurologic syndromes associated with high levels of antibodies to the voltage-gated potassium channel (VGKC) complex. Recent studies suggest that the antigenic target may be secreted proteins that bind to the VGKC complex, most frequently leucine-rich, gliomainactivated 1 (LGI1), and sometimes contactinassociated protein-like 2 (CASPR2) [1,2]. Additional specificities remain undefined. Patients with LE due to anti-VGKC/LGI1 autoantibodies present with subacute onset of short-term memory impairment, disorientation, hallucinations, agitation, seizures, abnormal behavior, and sleep disturbances. Usually patients are hyponatremic and do not have underlying malignancy [3]. Symptoms often improve as immunomodulatory therapies—including therapeutic plasma exchange (TPE)—decrease antibody titers. However, the optimal treatment regimen remains ill-defined. A paucity of literature addresses the role of TPE in treating this disease. CASE REPORT
A 69-year-old previously healthy man presented in May of 2011 with three months of right arm “myoclonus,” memory loss, delusions, and emotional C 2015 Wiley Periodicals, Inc. V
lability. After extensive workup first as an outpatient, then as an inpatient, a paraneoplastic antibody panel on cerebrospinal fluid sent to a commercial reference laboratory returned with an anti-VGKC antibody titer of 695 pmol/L (positive > 650 pmol/L). He was also hyponatremic (132 mmol/L). A PET scan was negative for malignancy. Initially, he underwent an inpatient 5day course of IVIG with 3 days of IV methylprednisolone. At discharge, he began long-term oral prednisone and continued symptomatic therapy with risperidone (an anti-psychotic) and primidone (a medication used in the setting of tremors/seizures). Upon outpatient follow-up, he showed improvement in memory with resolution of hallucinations and partial resolution of involuntary movements. Prednisone was discontinued in September 2011 due to elevated liver enzymes. He completed additional courses of IV methylprednisolone and IVIG in September and December 2011 respectively, and then started mycophenolate for long-term therapy. In June 2012, the patient continued to have *Correspondence to: Isabella W. Martin, Dartmouth-Hitchcock Medical Center, Department of Pathology, Lebanon, NH 03766. E-mail: [email protected] Received 1 December 2014; Accepted 7 March 2015 Published online 7 April 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jca.21395
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Fig. 1. Treatment course and anti-VGKC antibody levels measured at two reference laboratories using different test methodologies (radioimmunoassay at one and indirect immunofluorescence followed by immunoprecipitation at the other) over time.
episodes of myoclonus so his dose of mycophenolate was increased. In July, his wife expressed concerns about the patient’s poor balance and his bone density. A DEXA scan showed osteoporosis, possibly secondary to steroid therapy. He therefore initiated a course of TPE as an alternative treatment regimen (1.0 plasma volume, R Spectra and Spectra 5% albumin replacement; COBEV Optia, Terumo BCT, Lakewood, CO). He underwent twice weekly TPE procedures for three weeks in August 2012—six procedures in total. His anti-VGKC antibody level, tested by two different reference labs due to a combination of cost effectiveness and provider preference, decreased from pre-procedure to immediately following his course (see Fig. 1). Follow-up antibody levels over the next 2 years were either negative when tested by radioimmunoassay method at one reference laboratory or in the low-positive range when tested by indirect immunofluorescence followed by immunoprecipitation at another reference laboratory. He discontinued mycophenolate in August 2013, one year after his course of TPE. At most recent follow-up in January 2014 (18 months following TPE), his symptoms were well-controlled and his antibody titer was within normal range. Journal of Clinical Apheresis DOI 10.1002/jca
DISCUSSION
The 2013 ASFA guidelines categorize VGKC antibody-related diseases as a Category II recommendation meaning TPE is strongly recommended as a second-line therapy either stand-alone or in conjunction with other modalities [4]. However, this recommendation is based on low- or very low-quality evidence (Grade 1C) consisting of case reports. These case reports contain minimal specific description of TPE course and describe patients who receive several treatment modalities. In 2012, Jaben and Winters reviewed the literature and identified 13 cases of anti-VGKCassociated LE treated with PE, adding four cases of their own [5]. Since that publication, two case series included four more LE patients who received TPE of undefined course as part of their treatment regimen [6,7]. Our patient adds to the literature one new case of TPE used to treat LE. Moreover, TPE offered a viable alternative to long-term steroid use and its sideeffects. Our patient’s laboratory values have not completely normalized. His follow-up anti-VGKC antibody levels
Plasma Exchange in Limbic Encephalitis
have been either negative or in the low-positive range, depending on test methodology. There is currently no gold standard for anti-VGKC antibody testing. This case therefore highlights the possible discrepancies that can arise when different testing methods and different reference laboratories are used to follow a single patient’s course. One recent study suggests that the presence of low-level antibodies can be clinically significant [1]. However, our patient remains symptomfree. Although reflex testing for LGI1 and CASPR2 specificity has now become available commercially, we do not know the specificity of this patient’s antiVGKC autoantibodies. Like most other described cases, multiple modalities were used in treatment. The patient’s clinical success therefore cannot be attributed to TPE alone. However, the patient subjectively noted a temporal relation between lasting symptom improvement and his course of TPE. It is therefore likely that TPE played an important and steroid-sparing role in his long-term clinical remission. In light of the lack of sufficient published literature informing treatment approach in this disease, development of a rare disease registry to include LE due to anti-VGKC/LGI1 antibodies would be beneficial.
65
REFERENCES 1. Klein CJ, Lennon VA, Aston PA, McKeon A, O’Toole O, Quek A, Pittock SJ. Insights from LGI1 and CASPR2 potassium channel complex autoantibody subtyping. JAMA Neurol 2013;70: 229–234. 2. Kegel L, Aunin E, Meijer D, Bermingham JR. LGI proteins in the nervous system. ASN Neuro 2013;5:167–181. 3. Irani SR, Michell AW, Lang B, Pettingill P, Waters P, Johnson MR, Schott JM, Armstrong RJ, S Zagami A, Bleasel A, Somerville ER, Smith SM, Vincent A. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol 2011;69: 892–900. 4. Schwartz J, Winters JL, Padmanabhan A, Balogun RA, Delaney M, Linenberger ML, Szczepiorkowski ZM, Williams ME, Wu Y, Shaz BH. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the writing committee of the American society for apheresis: the sixth special issue. J Clin Apher 2013;28:145–284. 5. Jaben EA, Winters JL. Plasma exchange as a therapeutic option in patients with neurologic symptoms due to antibodies to voltage-gated potassium channels: a report of five cases and review of the literature. J Clin Apher 2012;27:267–273. 6. Shin YW, Lee ST, Shin JW, Moon J, Lim JA, Byun JI, Kim TJ, Lee KJ, Kim YS, Park KI, Jung KH, Lee SK, Chu K. VGKC-complex/ LGI1-antibody encephalitis: clinical manifestations and response to immunotherapy. J Neuroimmunol 2013;265:75–81. 7. Irani SR, Gelfand JM, Bettcher BM, Singhal NS, Geschwind MD. Effect of rituximab in patients with leucine-rich, gliomainactivated 1 antibody-associated encephalopathy. JAMA Neurol 2014;71:896–900.
Journal of Clinical Apheresis DOI 10.1002/jca
Case Report Therapeutic Plasma Exchange as a Steroid-Sparing Therapy in a Patient with Limbic Encephalitis Due to Antibodies to Voltage-Gated Potassium Channels Isabella W. Martin,1* Christi-Lynn B. Martin,1 Nancy M. Dunbar,1 Stephen L. Lee,2 and Zbigniew M. Szczepiorkowski1 1 2
Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire Department of Neurology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
Autoantibodies to the voltage-gated potassium channel (VGKC) complex cause a spectrum of non-paraneoplastic neurologic syndromes including limbic encephalitis (LE). We report a case of a man with LE who underwent a course of therapeutic plasma exchange (TPE) in addition to other immunomodulatory therapies and experienced sustained clinical resolution of his symptoms. This report adds to the existing literature supporting TPE in cases C 2015 Wiley Periodicals, Inc. of LE due to VGKC complex autoantibodies. J. Clin. Apheresis 31:63–65, 2016. V Key words: TPE; VGKC antibodies; LGI1antibodies
INTRODUCTION
Limbic encephalitis (LE) is one of several autoimmune, non-paraneoplastic, and variably treatable neurologic syndromes associated with high levels of antibodies to the voltage-gated potassium channel (VGKC) complex. Recent studies suggest that the antigenic target may be secreted proteins that bind to the VGKC complex, most frequently leucine-rich, gliomainactivated 1 (LGI1), and sometimes contactinassociated protein-like 2 (CASPR2) [1,2]. Additional specificities remain undefined. Patients with LE due to anti-VGKC/LGI1 autoantibodies present with subacute onset of short-term memory impairment, disorientation, hallucinations, agitation, seizures, abnormal behavior, and sleep disturbances. Usually patients are hyponatremic and do not have underlying malignancy [3]. Symptoms often improve as immunomodulatory therapies—including therapeutic plasma exchange (TPE)—decrease antibody titers. However, the optimal treatment regimen remains ill-defined. A paucity of literature addresses the role of TPE in treating this disease. CASE REPORT
A 69-year-old previously healthy man presented in May of 2011 with three months of right arm “myoclonus,” memory loss, delusions, and emotional C 2015 Wiley Periodicals, Inc. V
lability. After extensive workup first as an outpatient, then as an inpatient, a paraneoplastic antibody panel on cerebrospinal fluid sent to a commercial reference laboratory returned with an anti-VGKC antibody titer of 695 pmol/L (positive > 650 pmol/L). He was also hyponatremic (132 mmol/L). A PET scan was negative for malignancy. Initially, he underwent an inpatient 5day course of IVIG with 3 days of IV methylprednisolone. At discharge, he began long-term oral prednisone and continued symptomatic therapy with risperidone (an anti-psychotic) and primidone (a medication used in the setting of tremors/seizures). Upon outpatient follow-up, he showed improvement in memory with resolution of hallucinations and partial resolution of involuntary movements. Prednisone was discontinued in September 2011 due to elevated liver enzymes. He completed additional courses of IV methylprednisolone and IVIG in September and December 2011 respectively, and then started mycophenolate for long-term therapy. In June 2012, the patient continued to have *Correspondence to: Isabella W. Martin, Dartmouth-Hitchcock Medical Center, Department of Pathology, Lebanon, NH 03766. E-mail: [email protected] Received 1 December 2014; Accepted 7 March 2015 Published online 7 April 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jca.21395
64
Martin et al.
Fig. 1. Treatment course and anti-VGKC antibody levels measured at two reference laboratories using different test methodologies (radioimmunoassay at one and indirect immunofluorescence followed by immunoprecipitation at the other) over time.
episodes of myoclonus so his dose of mycophenolate was increased. In July, his wife expressed concerns about the patient’s poor balance and his bone density. A DEXA scan showed osteoporosis, possibly secondary to steroid therapy. He therefore initiated a course of TPE as an alternative treatment regimen (1.0 plasma volume, R Spectra and Spectra 5% albumin replacement; COBEV Optia, Terumo BCT, Lakewood, CO). He underwent twice weekly TPE procedures for three weeks in August 2012—six procedures in total. His anti-VGKC antibody level, tested by two different reference labs due to a combination of cost effectiveness and provider preference, decreased from pre-procedure to immediately following his course (see Fig. 1). Follow-up antibody levels over the next 2 years were either negative when tested by radioimmunoassay method at one reference laboratory or in the low-positive range when tested by indirect immunofluorescence followed by immunoprecipitation at another reference laboratory. He discontinued mycophenolate in August 2013, one year after his course of TPE. At most recent follow-up in January 2014 (18 months following TPE), his symptoms were well-controlled and his antibody titer was within normal range. Journal of Clinical Apheresis DOI 10.1002/jca
DISCUSSION
The 2013 ASFA guidelines categorize VGKC antibody-related diseases as a Category II recommendation meaning TPE is strongly recommended as a second-line therapy either stand-alone or in conjunction with other modalities [4]. However, this recommendation is based on low- or very low-quality evidence (Grade 1C) consisting of case reports. These case reports contain minimal specific description of TPE course and describe patients who receive several treatment modalities. In 2012, Jaben and Winters reviewed the literature and identified 13 cases of anti-VGKCassociated LE treated with PE, adding four cases of their own [5]. Since that publication, two case series included four more LE patients who received TPE of undefined course as part of their treatment regimen [6,7]. Our patient adds to the literature one new case of TPE used to treat LE. Moreover, TPE offered a viable alternative to long-term steroid use and its sideeffects. Our patient’s laboratory values have not completely normalized. His follow-up anti-VGKC antibody levels
Plasma Exchange in Limbic Encephalitis
have been either negative or in the low-positive range, depending on test methodology. There is currently no gold standard for anti-VGKC antibody testing. This case therefore highlights the possible discrepancies that can arise when different testing methods and different reference laboratories are used to follow a single patient’s course. One recent study suggests that the presence of low-level antibodies can be clinically significant [1]. However, our patient remains symptomfree. Although reflex testing for LGI1 and CASPR2 specificity has now become available commercially, we do not know the specificity of this patient’s antiVGKC autoantibodies. Like most other described cases, multiple modalities were used in treatment. The patient’s clinical success therefore cannot be attributed to TPE alone. However, the patient subjectively noted a temporal relation between lasting symptom improvement and his course of TPE. It is therefore likely that TPE played an important and steroid-sparing role in his long-term clinical remission. In light of the lack of sufficient published literature informing treatment approach in this disease, development of a rare disease registry to include LE due to anti-VGKC/LGI1 antibodies would be beneficial.
65
REFERENCES 1. Klein CJ, Lennon VA, Aston PA, McKeon A, O’Toole O, Quek A, Pittock SJ. Insights from LGI1 and CASPR2 potassium channel complex autoantibody subtyping. JAMA Neurol 2013;70: 229–234. 2. Kegel L, Aunin E, Meijer D, Bermingham JR. LGI proteins in the nervous system. ASN Neuro 2013;5:167–181. 3. Irani SR, Michell AW, Lang B, Pettingill P, Waters P, Johnson MR, Schott JM, Armstrong RJ, S Zagami A, Bleasel A, Somerville ER, Smith SM, Vincent A. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol 2011;69: 892–900. 4. Schwartz J, Winters JL, Padmanabhan A, Balogun RA, Delaney M, Linenberger ML, Szczepiorkowski ZM, Williams ME, Wu Y, Shaz BH. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the writing committee of the American society for apheresis: the sixth special issue. J Clin Apher 2013;28:145–284. 5. Jaben EA, Winters JL. Plasma exchange as a therapeutic option in patients with neurologic symptoms due to antibodies to voltage-gated potassium channels: a report of five cases and review of the literature. J Clin Apher 2012;27:267–273. 6. Shin YW, Lee ST, Shin JW, Moon J, Lim JA, Byun JI, Kim TJ, Lee KJ, Kim YS, Park KI, Jung KH, Lee SK, Chu K. VGKC-complex/ LGI1-antibody encephalitis: clinical manifestations and response to immunotherapy. J Neuroimmunol 2013;265:75–81. 7. Irani SR, Gelfand JM, Bettcher BM, Singhal NS, Geschwind MD. Effect of rituximab in patients with leucine-rich, gliomainactivated 1 antibody-associated encephalopathy. JAMA Neurol 2014;71:896–900.
Journal of Clinical Apheresis DOI 10.1002/jca
