598
Case Reports / Journal of Clinical Neuroscience 22 (2015) 598–600
4. Conclusion We report a patient with unexpected complete cage migration into the superior adjacent lumbar vertebral body almost 20 years after PLIF. The known risk factors for cage migration/subsidence should be considered during the follow-up of patients after lumbar interbody fusion surgery. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Fig. 1. Preoperative lumbar MRI showing signs of adjacent segment disease with a posterolateral protrusion at L3/4 on the right side, complete fusion at L4/5 and L5/S1 and an entirely migrated interbody fusion cage (on the left) into the superior adjacent vertebral body (L3). (A) Sagittal T2-weighted image and (B) axial T2-weighted image in the plane of the lines on the sagittal image.
fusion surgery, and a pear-shaped disc space on lateral radiographs are risk factors for a cage retropulsion (Table 1) [3]. A cage subsidence is usually defined as a migration of P2 mm into the adjacent vertebral body [4]. The incidence of cage subsidence after lumbar interbody fusion surgery varies greatly, depending on the exact surgical technique, the extent of endplate preparation, the cage type and size, and the degree of osteoporosis, reaching a rate of up to 76.7% [1,4]. Kim et al. identified the level of L5/S1 and anterior positioning of the cage as possible risk factors for cage subsidence [1]. Marchi et al. concluded that wider cages might avoid cage subsidence and better restore segmental lordosis in stand-alone lateral interbody fusion [5].
References [1] Kim MC, Chung HT, Cho JL, et al. Subsidence of polyetheretherketone cage after minimally invasive transforaminal lumbar interbody fusion. J Spinal Disord Tech 2013;26:87–92. [2] Gautschi OP, Schatlo B, Schaller K, et al. Clinically relevant complications related to pedicle screw placement in thoracolumbar surgery and their management: a literature review of 35,630 pedicle screws. Neurosurg Focus 2011;31:E8. [3] Kimura H, Shikata J, Odate S, et al. Risk factors for cage retropulsion after posterior lumbar interbody fusion: analysis of 1070 cases. Spine (Phila Pa 1976) 2012;37:1164–9. [4] Choi JY, Sung KH. Subsidence after anterior lumbar interbody fusion using paired stand-alone rectangular cages. Eur Spine J 2006;15:16–22. [5] Marchi L, Abdala N, Oliveira L, et al. Radiographic and clinical evaluation of cage subsidence after stand-alone lateral interbody fusion. J Neurosurg Spine 2013;19:110–8.
http://dx.doi.org/10.1016/j.jocn.2014.08.016
Treatment of progressive multifocal leukoencephalopathy–immune reconstitution inflammatory syndrome with intravenous immunoglobulin in a patient with multiple sclerosis treated with fingolimod after discontinuation of natalizumab Z. Calic a,b, C. Cappelen-Smith a,b,⇑, S.J. Hodgkinson a,b, A. McDougall a,b, R. Cuganesan c, B.J. Brew d a
Department of Neurology and Neurophysiology, Liverpool Hospital, Locked Bag 7103, Liverpool BC, NSW 1871, Australia South Western Sydney Clinical School, University of New South Wales, Sydney, NSW, Australia Department of Radiology, Liverpool Hospital, Liverpool BC, NSW, Australia d Department of Neurology, St Vincent’s Hospital, Darlinghurst, NSW, Australia b c
a r t i c l e
i n f o
Article history: Received 14 April 2014 Accepted 3 August 2014
Keywords: Fingolimod Intravenous immunoglobulin Natalizumab PML–IRIS
a b s t r a c t We report a case of progressive multifocal leukoencephalopathy–immune reconstitution inflammatory syndrome in a multiple sclerosis (MS) patient 3.5 months after fingolimod commencement and 4.5 months after natalizumab (NTZ) cessation. Three cerebrospinal fluid analyses were required before a definitive diagnosis of progressive multifocal leukoencephalopathy was reached. Intravenous immunoglobulin (IVIG) was subsequently given as the sole MS treatment along with mirtazapine and mefloquine. There has been improvement and subsequent clinical stabilization. The notable features are the difficult timing of fingolimod commencement in the context of previous NTZ therapy, the role of repeated cerebrospinal fluid John Cunningham virus analyses in progressive multifocal leukoencephalopathy diagnosis, and the role of IVIG. Crown Copyright Ó 2014 Published by Elsevier Ltd. All rights reserved.
⇑ Corresponding author. Tel.: +61 2 8738 3646; fax: +61 2 8738 3648. E-mail address: [email protected] (C. Cappelen-Smith).
Case Reports / Journal of Clinical Neuroscience 22 (2015) 598–600
599
1. Introduction Progressive multifocal leukoencephalopathy (PML) is an opportunistic, demyelinating central nervous system infection caused by the John Cunningham virus (JCV). Multiple sclerosis (MS) patients with natalizumab (NTZ) associated PML usually develop immune reconstitution inflammatory syndrome (IRIS) following discontinuation of NTZ. IRIS is characterized by neurological deterioration in the context of enlargement and gadolinium (Gd) enhancement of PML lesions on MRI [1]. Fingolimod is a common switch choice after NTZ therapy, especially for patients who have been taking NTZ for more than 24 months and are positive for serum anti-JCV antibodies. Clinical deterioration after changing to fingolimod may be caused by MS reactivation or relapse [2]. We report a woman with PML–IRIS diagnosed 3.5 months after starting fingolimod and 4.5 months after ceasing NTZ, which was discontinued after 4 years on the detection of serum anti-JCV antibodies. Clinical deterioration, which was initially diagnosed as a MS relapse was treated with intravenous methylprednisolone (MP) without benefit. Investigations confirmed PML–IRIS. Fingolimod was ceased and she received an induction course of intravenous immunoglobulin (IVIG) and oral mirtazapine and mefloquine with significant clinical improvement. 2. Case report A 35-year-old woman with relapsing-remitting MS was commenced on NTZ having previously failed interferon-beta and glatiramer acetate. She underwent 6 monthly clinical and radiological reviews and had no clinical relapses or new lesions on progress MRI. Her Expanded Disability Status Scale (EDSS) score was 2. NTZ was discontinued after 4 years (55 infusions) on detection of serum anti-JCV antibodies due to the risk of PML. Fingolimod was commenced 5 weeks after the final NTZ infusion. Shortly after commencing fingolimod she developed a headache and left hemiparesis. MRI of her brain showed a new region of subcortical T2-weighted hyperintensity in the right frontal lobe. Two courses of intravenous MP were given over the next 2 months for suspected acute MS relapses without significant benefit. Four months post-NTZ cessation, a repeat MRI was unchanged (Fig. 1A). Four and a half months after NTZ discontinuation, she developed progressive cognitive disturbance, fluctuating left arm weakness and 10 kg of weight loss. Examination revealed a left facial and upper limb paresis and generalized hyperreflexia. Her EDSS score was 5.5. A repeat MRI of the brain showed confluent Gdenhancing right frontal lobe abnormalities (Fig. 1B, E) suspicious for PML–IRIS. Fingolimod was then ceased. JCV DNA testing on the first cerebrospinal fluid (CSF) sample was negative in two laboratories. In a repeat CSF sample collected 1 week later JCV DNA was detected at low copy number (1/100. Fingolimod has become a common switch choice prescribed for patients previously on NTZ. The appropriate time interval between NTZ cessation and commencement of fingolimod is not established. A recent study recommended a gap of less than 2 months to reduce the risk of disease reactivation [2]. This patient demonstrates that clinical deterioration after switching to fingolimod may be caused by PML–IRIS related to prior NTZ therapy. To our knowledge only two previous PML cases have been reported in patients taking fingolimod and one was also linked to prior NTZ therapy [3,4]. The other patient was recently reported and remains under investigation [4]. JCV DNA in our patient’s CSF was initially negative and three CSF analyses were required before a definitive diagnosis was achieved, emphasizing the importance of repeat testing [1]. There are limited therapeutic options for PML–IRIS in NTZtreated MS patients. The mainstay is NTZ discontinuation followed by plasmapheresis [1]. There are no methods to hasten the elimination of fingolimod which has a half-life of 6–9 days. Antiviral drugs have no proven in vivo effect against JCV. Mefloquine, an antimalarial drug, and mirtazapine, a serotonin receptor antagonist, have been used on the basis of in vitro activity against JCV replication [1]. IRIS results from the restoration of central nervous system immune surveillance which is vital for controlling JCV but may cause initial worsening of neurological symptoms [1]. Clinical improvement has been reported after high dose intravenous steroid treatment of IRIS [1,5]. In our patient steroids and fingolimod did not prevent the development of IRIS. Maraviroc, a chemokinereceptor 5 antagonist, has recently shown promise in the prevention and treatment of IRIS [6]. There is limited information on the use of IVIG in MS patients with NTZ-associated PML–IRIS. Prior publications are limited to case reports [5,7] where IVIG was given to treat IRIS, in which one patient significantly improved [7], another survived [5] and one died from renal failure [5]. Our patient was given an induction course of IVIG aiming to modulate the IRIS process. Whilst our patient improved following IVIG, it must be noted that MS patients with NTZ-associated PML–IRIS may recover without specific therapy, and our patient’s initial clinical improvement may reflect the natural course of the illness. However, our patient’s clinical condition had worsened for 2 months prior to the IVIG treatment http://dx.doi.org/10.1016/j.jocn.2014.08.016
despite receiving high dose intravenous steroids. We postulate that IVIG contributed to her favorable outcome as her clinical condition clearly improved following IVIG. The cessation of fingolimod and/ or addition of mefloquine and mirtazapine may have also contributed to her clinical improvement. IVIG is an evidence based treatment for patients with relapsingremitting MS when first-line agents are contraindicated with a proven reduction in relapse rate and disability progression [8]. Our patient remains relapse-free at 16 months on a regimen of monthly infusions without the addition of other MS disease modulators. This case highlights the importance of clinical and radiological vigilance for PML after discontinuation of NTZ. An initial negative result for JCV DNA in the CSF does not exclude the diagnosis of PML and repeat testing is recommended. In addition, IVIG therapy may be useful in the acute management of PML–IRIS and in prevention of MS relapses in patients with NTZ-associated PML. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References [1] Brew BJ, Davies NW, Cinque P, et al. Progressive multifocal leukoencephalopathy and other forms of JC virus disease. Nat Rev Neurol 2010;6:667–79. [2] Jokubaitis VG, Li V, Kalincik T, et al. Fingolimod after natalizumab and the risk of short-term relapse. Neurology 2014;82:1204–11. [3] Fingolimod recipient develops PML, likely linked to natalizumab. React Wkly 2012;1399:3. [4] Carruthers RL, Berger J. Progressive multifocal leukoencephalopathy and JC Virus-related disease in modern neurology practice. Mult Scler Relat Disord 2014;3:419–30. [5] Clifford DB, De Luca A, Simpson DM, et al. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol 2010;9:438–46. [6] Giacomini PS, Rozenberg A, Metz I, et al. Maraviroc and JC Virus-associated immune reconstitution inflammatory syndrome. N Engl J Med 2014;370:486–8. [7] Kuhle J, Gosert R, Buhler R, et al. Management and outcome of CSF-JC virus PCRnegative PML in a natalizumab-treated patient with MS. Neurology 2011;77: 2010–6. [8] Soelberg Sorensen P. Intravenous polyclonal human immunoglobulins in multiple sclerosis. Neurodegener Dis 2008;5:8–15.
Case Reports / Journal of Clinical Neuroscience 22 (2015) 598–600
4. Conclusion We report a patient with unexpected complete cage migration into the superior adjacent lumbar vertebral body almost 20 years after PLIF. The known risk factors for cage migration/subsidence should be considered during the follow-up of patients after lumbar interbody fusion surgery. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Fig. 1. Preoperative lumbar MRI showing signs of adjacent segment disease with a posterolateral protrusion at L3/4 on the right side, complete fusion at L4/5 and L5/S1 and an entirely migrated interbody fusion cage (on the left) into the superior adjacent vertebral body (L3). (A) Sagittal T2-weighted image and (B) axial T2-weighted image in the plane of the lines on the sagittal image.
fusion surgery, and a pear-shaped disc space on lateral radiographs are risk factors for a cage retropulsion (Table 1) [3]. A cage subsidence is usually defined as a migration of P2 mm into the adjacent vertebral body [4]. The incidence of cage subsidence after lumbar interbody fusion surgery varies greatly, depending on the exact surgical technique, the extent of endplate preparation, the cage type and size, and the degree of osteoporosis, reaching a rate of up to 76.7% [1,4]. Kim et al. identified the level of L5/S1 and anterior positioning of the cage as possible risk factors for cage subsidence [1]. Marchi et al. concluded that wider cages might avoid cage subsidence and better restore segmental lordosis in stand-alone lateral interbody fusion [5].
References [1] Kim MC, Chung HT, Cho JL, et al. Subsidence of polyetheretherketone cage after minimally invasive transforaminal lumbar interbody fusion. J Spinal Disord Tech 2013;26:87–92. [2] Gautschi OP, Schatlo B, Schaller K, et al. Clinically relevant complications related to pedicle screw placement in thoracolumbar surgery and their management: a literature review of 35,630 pedicle screws. Neurosurg Focus 2011;31:E8. [3] Kimura H, Shikata J, Odate S, et al. Risk factors for cage retropulsion after posterior lumbar interbody fusion: analysis of 1070 cases. Spine (Phila Pa 1976) 2012;37:1164–9. [4] Choi JY, Sung KH. Subsidence after anterior lumbar interbody fusion using paired stand-alone rectangular cages. Eur Spine J 2006;15:16–22. [5] Marchi L, Abdala N, Oliveira L, et al. Radiographic and clinical evaluation of cage subsidence after stand-alone lateral interbody fusion. J Neurosurg Spine 2013;19:110–8.
http://dx.doi.org/10.1016/j.jocn.2014.08.016
Treatment of progressive multifocal leukoencephalopathy–immune reconstitution inflammatory syndrome with intravenous immunoglobulin in a patient with multiple sclerosis treated with fingolimod after discontinuation of natalizumab Z. Calic a,b, C. Cappelen-Smith a,b,⇑, S.J. Hodgkinson a,b, A. McDougall a,b, R. Cuganesan c, B.J. Brew d a
Department of Neurology and Neurophysiology, Liverpool Hospital, Locked Bag 7103, Liverpool BC, NSW 1871, Australia South Western Sydney Clinical School, University of New South Wales, Sydney, NSW, Australia Department of Radiology, Liverpool Hospital, Liverpool BC, NSW, Australia d Department of Neurology, St Vincent’s Hospital, Darlinghurst, NSW, Australia b c
a r t i c l e
i n f o
Article history: Received 14 April 2014 Accepted 3 August 2014
Keywords: Fingolimod Intravenous immunoglobulin Natalizumab PML–IRIS
a b s t r a c t We report a case of progressive multifocal leukoencephalopathy–immune reconstitution inflammatory syndrome in a multiple sclerosis (MS) patient 3.5 months after fingolimod commencement and 4.5 months after natalizumab (NTZ) cessation. Three cerebrospinal fluid analyses were required before a definitive diagnosis of progressive multifocal leukoencephalopathy was reached. Intravenous immunoglobulin (IVIG) was subsequently given as the sole MS treatment along with mirtazapine and mefloquine. There has been improvement and subsequent clinical stabilization. The notable features are the difficult timing of fingolimod commencement in the context of previous NTZ therapy, the role of repeated cerebrospinal fluid John Cunningham virus analyses in progressive multifocal leukoencephalopathy diagnosis, and the role of IVIG. Crown Copyright Ó 2014 Published by Elsevier Ltd. All rights reserved.
⇑ Corresponding author. Tel.: +61 2 8738 3646; fax: +61 2 8738 3648. E-mail address: [email protected] (C. Cappelen-Smith).
Case Reports / Journal of Clinical Neuroscience 22 (2015) 598–600
599
1. Introduction Progressive multifocal leukoencephalopathy (PML) is an opportunistic, demyelinating central nervous system infection caused by the John Cunningham virus (JCV). Multiple sclerosis (MS) patients with natalizumab (NTZ) associated PML usually develop immune reconstitution inflammatory syndrome (IRIS) following discontinuation of NTZ. IRIS is characterized by neurological deterioration in the context of enlargement and gadolinium (Gd) enhancement of PML lesions on MRI [1]. Fingolimod is a common switch choice after NTZ therapy, especially for patients who have been taking NTZ for more than 24 months and are positive for serum anti-JCV antibodies. Clinical deterioration after changing to fingolimod may be caused by MS reactivation or relapse [2]. We report a woman with PML–IRIS diagnosed 3.5 months after starting fingolimod and 4.5 months after ceasing NTZ, which was discontinued after 4 years on the detection of serum anti-JCV antibodies. Clinical deterioration, which was initially diagnosed as a MS relapse was treated with intravenous methylprednisolone (MP) without benefit. Investigations confirmed PML–IRIS. Fingolimod was ceased and she received an induction course of intravenous immunoglobulin (IVIG) and oral mirtazapine and mefloquine with significant clinical improvement. 2. Case report A 35-year-old woman with relapsing-remitting MS was commenced on NTZ having previously failed interferon-beta and glatiramer acetate. She underwent 6 monthly clinical and radiological reviews and had no clinical relapses or new lesions on progress MRI. Her Expanded Disability Status Scale (EDSS) score was 2. NTZ was discontinued after 4 years (55 infusions) on detection of serum anti-JCV antibodies due to the risk of PML. Fingolimod was commenced 5 weeks after the final NTZ infusion. Shortly after commencing fingolimod she developed a headache and left hemiparesis. MRI of her brain showed a new region of subcortical T2-weighted hyperintensity in the right frontal lobe. Two courses of intravenous MP were given over the next 2 months for suspected acute MS relapses without significant benefit. Four months post-NTZ cessation, a repeat MRI was unchanged (Fig. 1A). Four and a half months after NTZ discontinuation, she developed progressive cognitive disturbance, fluctuating left arm weakness and 10 kg of weight loss. Examination revealed a left facial and upper limb paresis and generalized hyperreflexia. Her EDSS score was 5.5. A repeat MRI of the brain showed confluent Gdenhancing right frontal lobe abnormalities (Fig. 1B, E) suspicious for PML–IRIS. Fingolimod was then ceased. JCV DNA testing on the first cerebrospinal fluid (CSF) sample was negative in two laboratories. In a repeat CSF sample collected 1 week later JCV DNA was detected at low copy number (1/100. Fingolimod has become a common switch choice prescribed for patients previously on NTZ. The appropriate time interval between NTZ cessation and commencement of fingolimod is not established. A recent study recommended a gap of less than 2 months to reduce the risk of disease reactivation [2]. This patient demonstrates that clinical deterioration after switching to fingolimod may be caused by PML–IRIS related to prior NTZ therapy. To our knowledge only two previous PML cases have been reported in patients taking fingolimod and one was also linked to prior NTZ therapy [3,4]. The other patient was recently reported and remains under investigation [4]. JCV DNA in our patient’s CSF was initially negative and three CSF analyses were required before a definitive diagnosis was achieved, emphasizing the importance of repeat testing [1]. There are limited therapeutic options for PML–IRIS in NTZtreated MS patients. The mainstay is NTZ discontinuation followed by plasmapheresis [1]. There are no methods to hasten the elimination of fingolimod which has a half-life of 6–9 days. Antiviral drugs have no proven in vivo effect against JCV. Mefloquine, an antimalarial drug, and mirtazapine, a serotonin receptor antagonist, have been used on the basis of in vitro activity against JCV replication [1]. IRIS results from the restoration of central nervous system immune surveillance which is vital for controlling JCV but may cause initial worsening of neurological symptoms [1]. Clinical improvement has been reported after high dose intravenous steroid treatment of IRIS [1,5]. In our patient steroids and fingolimod did not prevent the development of IRIS. Maraviroc, a chemokinereceptor 5 antagonist, has recently shown promise in the prevention and treatment of IRIS [6]. There is limited information on the use of IVIG in MS patients with NTZ-associated PML–IRIS. Prior publications are limited to case reports [5,7] where IVIG was given to treat IRIS, in which one patient significantly improved [7], another survived [5] and one died from renal failure [5]. Our patient was given an induction course of IVIG aiming to modulate the IRIS process. Whilst our patient improved following IVIG, it must be noted that MS patients with NTZ-associated PML–IRIS may recover without specific therapy, and our patient’s initial clinical improvement may reflect the natural course of the illness. However, our patient’s clinical condition had worsened for 2 months prior to the IVIG treatment http://dx.doi.org/10.1016/j.jocn.2014.08.016
despite receiving high dose intravenous steroids. We postulate that IVIG contributed to her favorable outcome as her clinical condition clearly improved following IVIG. The cessation of fingolimod and/ or addition of mefloquine and mirtazapine may have also contributed to her clinical improvement. IVIG is an evidence based treatment for patients with relapsingremitting MS when first-line agents are contraindicated with a proven reduction in relapse rate and disability progression [8]. Our patient remains relapse-free at 16 months on a regimen of monthly infusions without the addition of other MS disease modulators. This case highlights the importance of clinical and radiological vigilance for PML after discontinuation of NTZ. An initial negative result for JCV DNA in the CSF does not exclude the diagnosis of PML and repeat testing is recommended. In addition, IVIG therapy may be useful in the acute management of PML–IRIS and in prevention of MS relapses in patients with NTZ-associated PML. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References [1] Brew BJ, Davies NW, Cinque P, et al. Progressive multifocal leukoencephalopathy and other forms of JC virus disease. Nat Rev Neurol 2010;6:667–79. [2] Jokubaitis VG, Li V, Kalincik T, et al. Fingolimod after natalizumab and the risk of short-term relapse. Neurology 2014;82:1204–11. [3] Fingolimod recipient develops PML, likely linked to natalizumab. React Wkly 2012;1399:3. [4] Carruthers RL, Berger J. Progressive multifocal leukoencephalopathy and JC Virus-related disease in modern neurology practice. Mult Scler Relat Disord 2014;3:419–30. [5] Clifford DB, De Luca A, Simpson DM, et al. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol 2010;9:438–46. [6] Giacomini PS, Rozenberg A, Metz I, et al. Maraviroc and JC Virus-associated immune reconstitution inflammatory syndrome. N Engl J Med 2014;370:486–8. [7] Kuhle J, Gosert R, Buhler R, et al. Management and outcome of CSF-JC virus PCRnegative PML in a natalizumab-treated patient with MS. Neurology 2011;77: 2010–6. [8] Soelberg Sorensen P. Intravenous polyclonal human immunoglobulins in multiple sclerosis. Neurodegener Dis 2008;5:8–15.
