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Immune Checkpoint Inhibitor-Induced Limbic Encephalitis during Treatment with Atezolizumab in a Patient with Small-Cell Lung Cancer: A Case Report and Review of the Literature

Immune Checkpoint Inhibitor-Induced Limbic Encephalitis during Treatment with Atezolizumab in a... Hindawi Case Reports in Immunology Volume 2022, Article ID 9290922, 5 pages https://doi.org/10.1155/2022/9290922 Case Report Immune Checkpoint Inhibitor-Induced Limbic Encephalitis during Treatment with Atezolizumab in a Patient with Small-Cell Lung Cancer: A Case Report and Review of the Literature 1,2 1 1 1 Koki Nakashima , Yoshiki Demura, Kosuke Kurokawa, Toshihiro Takeda, 1 1 1 1 2 Norihiro Jikuya, Masahiro Oi, Toshihiko Tada, Masaya Akai, and Tamotsu Ishizuka Depertment of Respiratory Medicine, Japanese Red Cross Fukui Hospital, 2-4-1, Tsukimi, Fukui-Shi, Fukui-Ken, Japan "ird Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Shimoaizuki, Eiheiji-Cho, Matsuoka-Gun, Fukui-Ken, Japan Correspondence should be addressed to Koki Nakashima; kouk0527@yahoo.co.jp Received 17 July 2021; Revised 8 December 2021; Accepted 22 December 2021; Published 6 January 2022 Academic Editor: Ahmad Mansour Copyright © 2022 Koki Nakashima et al. *is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Paraneoplastic neurological syndrome (PNS) is associated with malignancies, including small-cell lung cancer. Recently, PNS cases among patients with small-cell lung cancer (SCLC) induced by immune checkpoint inhibitors have increased. We herein report a 66-year-old man with SCLC who developed disorientation, dysphagia, and gait disturbance after three courses of treatment with atezolizumab. Brain magnetic resonance imaging revealed a high-intensity area in the bilateral temporal lobes. Blood test results were positive for anti-Hu and anti-Zic4 antibodies, which led to the diagnosis of limbic encephalitis as PNS. Some symptoms improved with intravenous administration of steroids and immunoglobulins. 1. Introduction 2. Case Report Paraneoplastic neurological syndrome (PNS) is caused by an A 66-year-old man with a history of smoking for 40 years autoimmune process that develops in patients with any type was referred to our hospital for abnormal chest radiograph of malignancy [1, 2]. Immune checkpoint inhibitors (ICIs) findings. *e patient had a history of bronchial asthma, with are effective treatment options for patients with malig- no history of autoimmune diseases. Computed tomography nancies, including small-cell lung cancer (SCLC) [3]. (CT) and positron emission tomography with 18F-fluo- However, ICIs cause inflammatory side effects by increasing rodeoxyglucose revealed a tumor mass in the right hilum, the activity of the immune system [4]. *erefore, ICIs are hilar and mediastinal lymph node swelling, and multiple presumed to be a risk factor for PNS [5, 6]. In fact, cases of lung metastases. Brain magnetic resonance imaging (MRI) PNS induced by ICIs have recently increased [7–12]. showed no abnormal finding (Figure 1). Pathological Herein, we report a case of ICI-induced limbic en- findings of bronchoscopy of the primary tumor revealed cephalitis developed in a patient with SCLC. *e present SCLC. *erefore, the patient was diagnosed with extensive report suggests that clinicians should consider the possibility disease SCLC (ED-SCLC) and was treated with carboplatin of PNS when patients develop neurological symptoms after and etoposide, and atezolizumab was initiated as first-line ICI initiation. chemotherapy. Treatment led to a complete response. 2 Case Reports in Immunology Figure 1: Fluid-attenuated inversion recovery (FLAIR) image of Figure 2: FLAIR image of brain MRI after development of neu- brain magnetic resonance imaging (MRI) before initiation of rological symptoms reveals high-intensity area in bilateral temporal treatment with immune checkpoint inhibitor reveals no abnormal lobes (red arrowheads). finding. Zic4 antibodies were detected in the serum at the onset of *e patient developed disorientation after three courses neurological symptoms. (2) SCLC was presented at the onset of chemotherapy over 2 months. Although follow-up of neurological symptoms. (3) SCLC is one of the most without any treatment was continued, the disorientation strongly associated tumors with PNS [7–12]. (4) MRI worsened with coma. Dysphagia and gait disturbances due revealed a high-intensity area in the bilateral temporal lobes, to muscle weakness also developed; however, we could not which was consistent with limbic encephalitis. (5) No other perform detailed neurological examination owing to the possible cause was found for disorientation, such as central state of his consciousness. Fluid-attenuated inversion re- nervous system metastasis, stroke, or metabolic disorders in covery (FLAIR) imaging of brain MRI after coma devel- blood tests and brain MRI. (6) No evidence of meningeal opment showed a high-intensity area in the bilateral carcinomatosis or infection in the cerebrospinal fluid was temporal lobes (Figure 2). Furthermore, anti-Hu and anti- found. Zic4 antibodies were highly detected in the blood test. *e Anti-Hu antibody is an auto-antibody associated with cerebrospinal fluid examination showed no evidence of limbic encephalitis and sensory neuropathy [13]. Anti-Zic4 tumor cells or infection, including herpes simplex virus and antibody is also associated with limbic encephalitis, cere- varicella-zoster virus (Table 1). Based on these results, anti- bellar dysfunction, and sensory neuropathy [14]. *e MRI Hu and anti-Zic4 antibodies-positive limbic encephalitis as findings of the patient were consistent with those of limbic PNS was given as the final diagnosis. As steroid pulse therapy encephalitis. *erefore, the neurological symptoms, dis- was initiated, the disturbance of consciousness improved. turbance of consciousness, dysphagia, and gait disturbance However, dysphagia and gait disturbance showed no im- were considered to be caused by anti-Hu and anti-Zic4 provement. Due to this, intravenous immunoglobulin antibodies-positive limbic encephalitis as PNS in the present (IVIG) therapy was also initiated leading to improvement of case. Previous reports also showed several types of neuro- dysphagia, but not with gait disturbance. Brain MRI findings logical symptoms of PNS in SCLC patients treated with ICIs at 3 months after initiation of steroid treatment also im- (Table 2). However, a limitation of the present case is the proved slightly (Figure 3), and blood test at that time showed non-examination of the neuronal cell surface antibodies. anti-Zic4 antibody negativity with anti-Hu antibody Neuronal cell surface antibody-mediated autoimmune en- persistence. cephalitis should be considered as a differential diagnosis At the time of writing, 6 months have passed since the [15]. A diagnosis of anti-Hu and anti-Zic4 antibodies- development of limbic encephalitis, and the neurological positive limbic encephalitis may be more likely, if neuronal symptoms did not worsen. Furthermore, a complete re- cell surface antibodies, such as anti-n-methyl-D-aspartate sponse was observed. (NMDA) receptor antibody, are fount to be negative. ICI might have induced the neurological symptoms in 3. Discussion the present case, since one of the mechanisms of immune- In the present case, limbic encephalitis as PNS was diag- related adverse events is an increase in pre-existing auto- nosed due to the following reasons. (1) Anti-Hu and anti- antibodies [2, 12]. *e neurological symptoms occurred 2 Case Reports in Immunology 3 Table 1: Laboratory findings at the onset of PNS. Anti-neuronal antibodies Cerebrospinal fluid Amphiphysin Negative Appearance Clear CV2 Negative Cell count 5 /μl PNMA2 Negative Poly 0 % Ri Negative Mono 100 % Yo Negative Protein 94 mg/dl Hu 3+ Glucose 72 mg/dl Recoverin Negative ADA ≦1 U/l SOX1 Negative HSV-PCR Negative Titin Negative VZV-PCR Negative Zic4 3+ GAD65 Negative Cytology Class I Tr Negative Culture Negative ADA, adenosine deaminase; HSV, herpes simplex virus; VZV, varicella-zoster virus. Figure 3: FLAIR image of brain MRI after development of neurological symptoms reveals slight improvement of high-intensity area in bilateral temporal lobes (red arrowheads). months after the first initiation of ICI, similar to previous IVIG were used to treat PNS, and the disturbance of reports (Table 2). Moreover, ICI-activated autoantibodies consciousness and dysphagia improved. However, gait might be a reason why neurological symptoms were not disturbance did not improve. In previous cases, meth- ylprednisolone and IVIG were the most frequently used improved completely. *e persistence of neurological symptoms was also similar to previous reports (Table 2). ICI- treatments for PNS, but only a few patients had improved induced PNS cases may be relatively rare in non-small-cell neurological symptoms completely (Table 2). Informa- lung cancer patients, with only a few cases reported pre- tion about the appropriate treatments for PNS is needed viously [16, 17]. Clinicians should consider the possibility of in the future. PNS especially when patients with SCLC complain of *ere are some limitations of present case. First, neurological symptoms after initiation of ICIs, especially the examination of the neuronal cell surface antibodies after several months. was not performed. Second, other causes of limbic en- *ere is no established treatment for most cases of cephalitis, such as primary autoimmune encephalitis PNS. However, corticosteroids and other immunosup- or iatrogenic encephalopathy, could not be ruled out pressive drugs, such as cyclophosphamide or tacrolimus, completely. IVIG, and plasma exchange, are often used in clinical In conclusion, we described a case of ICI-induced limbic practice [1]. In the present case, methylprednisolone and encephalitis as PNS and reviewed the literature on cases of 4 Case Reports in Immunology Table 2: Details of cases of PNS induced by ICI in SCLC patients. Time to No. Age Sex Country ICI Antibody PNS PNS symptoms Treatment for PNS Outcome References onset Striatal 5 1 76 M Japan Atezolizumab CRMP5 Forgetfulnes, irritability Methylprednisolone Improved [7] encephalitis months Hu, Sensory Tactile and pain 1 month IVIG Not improved [8] 2 70 M Japan Atezolizumab SOX1 polyneuropathy disturbances 1.5 3 66 F China Sintilimab Hu Encephalitis Focal seizures Methylprednisolone Improved [9] months Numbness in hands and Sensory a few Methylprednisolone, 4 62 F USA Nivolumab Hu feet, tremor, loss of Not improved [10] polyneuropathy days IVIG dexterity, gait ataxia Limbic Short-term memory Methylprednisolone, Improved (not 5 71 F Switzerland Nivolumab + ipilimumab Hu 4 days [11] encephalitis deficits natalizumab completely) Sensory Painful paresthesia, gait 3 Methylprednisolone, Improved 6 46 M France Pembrolizumab Hu [12] neuropathy disturbance months IVIG (temporary) Dizziness, vomiting, 2 Improved (not 7 71 M France Atezolizumab Hu Encephalitis IVIG [12] diplopia, gait disturbance months completely) Present Limbic Disorientation, dysphagia, 2 Methylprednisolone, Improved (not 66 M Japan Atezolizumab Hu, Zic4 case encephalitis gait disturbance months IVIG completely) PNS, paraneoplastic neurological syndrome; ICI, immune checkpoint inhibitor; SCLC, small-cell lung cancer. Case Reports in Immunology 5 triggered by immune-checkpoint inhibitor treatment,” Jour- PNS induced by ICI in SCLC patients. Clinicians should nal of Neurology, vol. 267, no. 7, pp. 2154–2156, 2020. consider the possibility of PNS when patients with SCLC [13] F. Graus, F. Keime-Guibert, R. Reñe et al., “Anti-Hu-asso- develop neurological symptoms after ICI initiation. ciated paraneoplastic encephalomyelitis: analysis of 200 pa- tients,” Brain, vol. 124, no. 6, pp. 1138–1148, 2001. Conflicts of Interest [14] L. Bataller, D. F. Wade, F. Graus, H. D. Stacey, M. R. Rosenfeld, and J. Dalmau, “Antibodies to Zic4 in *e authors have no conflicts of interest directly relevant to paraneoplastic neurologic disorders and small-cell lung the content of this article to declare. cancer,” Neurology, vol. 62, no. 5, pp. 778–782, 2004. [15] Z. Hayden, B. Bon´ ´ e, G. Orsi et al., “Clinical characteristics and outcome of neuronal surface antibody-mediated autoimmune Acknowledgments encephalitis patients in a national cohort,” Frontiers in Neurology, vol. 12, Article ID 611597, 202. We would like to thank Editage (https://www.editage.com) [16] Y. Nakatani, N. Tanaka, T. Enami, S. Minami, T. Okazaki, and for providing English language editing assistance. K. Komuta, “Lambert-eaton myasthenic syndrome caused by nivolumab in a patient with squamous cell lung cancer,” Case Reports in Neurology, vol. 10, no. 3, pp. 346–352, 2018. References [17] K. Nakashima, Y. Fujii, M. Sato, K. Igarashi, M. Kobayashi, and T. Ishizuka, “A case of non-small cell lung cancer pre- [1] R. B. Darnell and J. B. Posner, “Paraneoplastic syndromes senting anti-amphiphysin antibody-positive paraneoplastic involving the nervous system,” New England Journal of neurological syndrome,” Respiratory Medicine Case Reports, Medicine, vol. 349, no. 16, pp. 1543–1554, 2003. vol. 34, Article ID 101525, 2021. [2] J. Dalmau and M. R. Rosenfeld, “Paraneoplastic syndromes of the CNS,” "e Lancet Neurology, vol. 7, no. 4, pp. 327–340, [3] L. Horn, A. S. Mansfield, A. Szcze˛sna et al., “First-line ate- zolizumab plus chemotherapy in extensive-stage small-cell lung cancer,” New England Journal of Medicine, vol. 379, no. 23, pp. 2220–2229, 2018. [4] M. A. Postow, R. Sidlow, and M. D. Hellmann, “Immune- related adverse events associated with immune checkpoint blockade,” New England Journal of Medicine, vol. 378, no. 2, pp. 158–168, 2018. [5] F. Graus and J. Dalmau, “Paraneoplastic neurological syn- dromes in the era of immune-checkpoint inhibitors,” Nature Reviews Clinical Oncology, vol. 16, no. 9, pp. 535–548, 2019. [6] A. Zekeridou and V. A. Lennon, “Neurologic autoimmunity in the era of checkpoint inhibitor cancer immunotherapy,” Mayo Clinic Proceedings, vol. 94, no. 9, pp. 1865–1878, 2019. [7] S. Tatsumi, K. Uryu, S. Iwasaki, and H. Harada, “A case of anti-CRMP5 paraneoplastic neurological syndrome induced by atezolizumab for small cell lung cancer,” Internal Medicine, (article in press), 2020. [8] T. Morimoto, T. Orihashi, K. Yamasaki, M. Tahara, K. Kato, and K. Yatera, “Paraneoplastic sensory polyneuropathy re- lated to anti-PD-L1-including anticancer treatment in a pa- tient with lung cancer,” Internal Medicine, vol. 60, no. 10, pp. 1577–1581, 2021. [9] K. Kang, K. Zheng, and Y. Zhang, “Paraneoplastic encephalitis and enteric neuropathy associated with anti-hu antibody in a patient following immune-checkpoint inhibitor therapy,” Journal of Immunotherapy (Hagerstown, Md: 1997), vol. 43, no. 5, pp. 165–168, 2020. [10] P. Raibagkar, D. Ho, K. S. Gunturu, and J. Srinivasan, “Worsening of anti-Hu paraneoplastic neurological syndrome related to anti-PD-1 treatment: case report and review of literature,” Journal of Neuroimmunology, vol. 341, Article ID 577184, 2020. [11] A. F. Hottinger, R. De Micheli, V. Guido, A. Karampera, P. Hagmann, and R. Du Pasquier, “Natalizumab may control immune checkpoint inhibitor-induced limbic encephalitis,” Neurology-Neuroimmunology Neuroinflammation, vol. 5, no. 2, p. e439, 2018. [12] N. Mongay-Ochoa, A. Vogrig, S. Muñiz-Castrillo, and J. Honnorat, “Anti-Hu-associated paraneoplastic syndromes http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Case Reports in Immunology Hindawi Publishing Corporation

Immune Checkpoint Inhibitor-Induced Limbic Encephalitis during Treatment with Atezolizumab in a Patient with Small-Cell Lung Cancer: A Case Report and Review of the Literature

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Hindawi Case Reports in Immunology Volume 2022, Article ID 9290922, 5 pages https://doi.org/10.1155/2022/9290922 Case Report Immune Checkpoint Inhibitor-Induced Limbic Encephalitis during Treatment with Atezolizumab in a Patient with Small-Cell Lung Cancer: A Case Report and Review of the Literature 1,2 1 1 1 Koki Nakashima , Yoshiki Demura, Kosuke Kurokawa, Toshihiro Takeda, 1 1 1 1 2 Norihiro Jikuya, Masahiro Oi, Toshihiko Tada, Masaya Akai, and Tamotsu Ishizuka Depertment of Respiratory Medicine, Japanese Red Cross Fukui Hospital, 2-4-1, Tsukimi, Fukui-Shi, Fukui-Ken, Japan "ird Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Shimoaizuki, Eiheiji-Cho, Matsuoka-Gun, Fukui-Ken, Japan Correspondence should be addressed to Koki Nakashima; kouk0527@yahoo.co.jp Received 17 July 2021; Revised 8 December 2021; Accepted 22 December 2021; Published 6 January 2022 Academic Editor: Ahmad Mansour Copyright © 2022 Koki Nakashima et al. *is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Paraneoplastic neurological syndrome (PNS) is associated with malignancies, including small-cell lung cancer. Recently, PNS cases among patients with small-cell lung cancer (SCLC) induced by immune checkpoint inhibitors have increased. We herein report a 66-year-old man with SCLC who developed disorientation, dysphagia, and gait disturbance after three courses of treatment with atezolizumab. Brain magnetic resonance imaging revealed a high-intensity area in the bilateral temporal lobes. Blood test results were positive for anti-Hu and anti-Zic4 antibodies, which led to the diagnosis of limbic encephalitis as PNS. Some symptoms improved with intravenous administration of steroids and immunoglobulins. 1. Introduction 2. Case Report Paraneoplastic neurological syndrome (PNS) is caused by an A 66-year-old man with a history of smoking for 40 years autoimmune process that develops in patients with any type was referred to our hospital for abnormal chest radiograph of malignancy [1, 2]. Immune checkpoint inhibitors (ICIs) findings. *e patient had a history of bronchial asthma, with are effective treatment options for patients with malig- no history of autoimmune diseases. Computed tomography nancies, including small-cell lung cancer (SCLC) [3]. (CT) and positron emission tomography with 18F-fluo- However, ICIs cause inflammatory side effects by increasing rodeoxyglucose revealed a tumor mass in the right hilum, the activity of the immune system [4]. *erefore, ICIs are hilar and mediastinal lymph node swelling, and multiple presumed to be a risk factor for PNS [5, 6]. In fact, cases of lung metastases. Brain magnetic resonance imaging (MRI) PNS induced by ICIs have recently increased [7–12]. showed no abnormal finding (Figure 1). Pathological Herein, we report a case of ICI-induced limbic en- findings of bronchoscopy of the primary tumor revealed cephalitis developed in a patient with SCLC. *e present SCLC. *erefore, the patient was diagnosed with extensive report suggests that clinicians should consider the possibility disease SCLC (ED-SCLC) and was treated with carboplatin of PNS when patients develop neurological symptoms after and etoposide, and atezolizumab was initiated as first-line ICI initiation. chemotherapy. Treatment led to a complete response. 2 Case Reports in Immunology Figure 1: Fluid-attenuated inversion recovery (FLAIR) image of Figure 2: FLAIR image of brain MRI after development of neu- brain magnetic resonance imaging (MRI) before initiation of rological symptoms reveals high-intensity area in bilateral temporal treatment with immune checkpoint inhibitor reveals no abnormal lobes (red arrowheads). finding. Zic4 antibodies were detected in the serum at the onset of *e patient developed disorientation after three courses neurological symptoms. (2) SCLC was presented at the onset of chemotherapy over 2 months. Although follow-up of neurological symptoms. (3) SCLC is one of the most without any treatment was continued, the disorientation strongly associated tumors with PNS [7–12]. (4) MRI worsened with coma. Dysphagia and gait disturbances due revealed a high-intensity area in the bilateral temporal lobes, to muscle weakness also developed; however, we could not which was consistent with limbic encephalitis. (5) No other perform detailed neurological examination owing to the possible cause was found for disorientation, such as central state of his consciousness. Fluid-attenuated inversion re- nervous system metastasis, stroke, or metabolic disorders in covery (FLAIR) imaging of brain MRI after coma devel- blood tests and brain MRI. (6) No evidence of meningeal opment showed a high-intensity area in the bilateral carcinomatosis or infection in the cerebrospinal fluid was temporal lobes (Figure 2). Furthermore, anti-Hu and anti- found. Zic4 antibodies were highly detected in the blood test. *e Anti-Hu antibody is an auto-antibody associated with cerebrospinal fluid examination showed no evidence of limbic encephalitis and sensory neuropathy [13]. Anti-Zic4 tumor cells or infection, including herpes simplex virus and antibody is also associated with limbic encephalitis, cere- varicella-zoster virus (Table 1). Based on these results, anti- bellar dysfunction, and sensory neuropathy [14]. *e MRI Hu and anti-Zic4 antibodies-positive limbic encephalitis as findings of the patient were consistent with those of limbic PNS was given as the final diagnosis. As steroid pulse therapy encephalitis. *erefore, the neurological symptoms, dis- was initiated, the disturbance of consciousness improved. turbance of consciousness, dysphagia, and gait disturbance However, dysphagia and gait disturbance showed no im- were considered to be caused by anti-Hu and anti-Zic4 provement. Due to this, intravenous immunoglobulin antibodies-positive limbic encephalitis as PNS in the present (IVIG) therapy was also initiated leading to improvement of case. Previous reports also showed several types of neuro- dysphagia, but not with gait disturbance. Brain MRI findings logical symptoms of PNS in SCLC patients treated with ICIs at 3 months after initiation of steroid treatment also im- (Table 2). However, a limitation of the present case is the proved slightly (Figure 3), and blood test at that time showed non-examination of the neuronal cell surface antibodies. anti-Zic4 antibody negativity with anti-Hu antibody Neuronal cell surface antibody-mediated autoimmune en- persistence. cephalitis should be considered as a differential diagnosis At the time of writing, 6 months have passed since the [15]. A diagnosis of anti-Hu and anti-Zic4 antibodies- development of limbic encephalitis, and the neurological positive limbic encephalitis may be more likely, if neuronal symptoms did not worsen. Furthermore, a complete re- cell surface antibodies, such as anti-n-methyl-D-aspartate sponse was observed. (NMDA) receptor antibody, are fount to be negative. ICI might have induced the neurological symptoms in 3. Discussion the present case, since one of the mechanisms of immune- In the present case, limbic encephalitis as PNS was diag- related adverse events is an increase in pre-existing auto- nosed due to the following reasons. (1) Anti-Hu and anti- antibodies [2, 12]. *e neurological symptoms occurred 2 Case Reports in Immunology 3 Table 1: Laboratory findings at the onset of PNS. Anti-neuronal antibodies Cerebrospinal fluid Amphiphysin Negative Appearance Clear CV2 Negative Cell count 5 /μl PNMA2 Negative Poly 0 % Ri Negative Mono 100 % Yo Negative Protein 94 mg/dl Hu 3+ Glucose 72 mg/dl Recoverin Negative ADA ≦1 U/l SOX1 Negative HSV-PCR Negative Titin Negative VZV-PCR Negative Zic4 3+ GAD65 Negative Cytology Class I Tr Negative Culture Negative ADA, adenosine deaminase; HSV, herpes simplex virus; VZV, varicella-zoster virus. Figure 3: FLAIR image of brain MRI after development of neurological symptoms reveals slight improvement of high-intensity area in bilateral temporal lobes (red arrowheads). months after the first initiation of ICI, similar to previous IVIG were used to treat PNS, and the disturbance of reports (Table 2). Moreover, ICI-activated autoantibodies consciousness and dysphagia improved. However, gait might be a reason why neurological symptoms were not disturbance did not improve. In previous cases, meth- ylprednisolone and IVIG were the most frequently used improved completely. *e persistence of neurological symptoms was also similar to previous reports (Table 2). ICI- treatments for PNS, but only a few patients had improved induced PNS cases may be relatively rare in non-small-cell neurological symptoms completely (Table 2). Informa- lung cancer patients, with only a few cases reported pre- tion about the appropriate treatments for PNS is needed viously [16, 17]. Clinicians should consider the possibility of in the future. PNS especially when patients with SCLC complain of *ere are some limitations of present case. First, neurological symptoms after initiation of ICIs, especially the examination of the neuronal cell surface antibodies after several months. was not performed. Second, other causes of limbic en- *ere is no established treatment for most cases of cephalitis, such as primary autoimmune encephalitis PNS. However, corticosteroids and other immunosup- or iatrogenic encephalopathy, could not be ruled out pressive drugs, such as cyclophosphamide or tacrolimus, completely. IVIG, and plasma exchange, are often used in clinical In conclusion, we described a case of ICI-induced limbic practice [1]. In the present case, methylprednisolone and encephalitis as PNS and reviewed the literature on cases of 4 Case Reports in Immunology Table 2: Details of cases of PNS induced by ICI in SCLC patients. Time to No. Age Sex Country ICI Antibody PNS PNS symptoms Treatment for PNS Outcome References onset Striatal 5 1 76 M Japan Atezolizumab CRMP5 Forgetfulnes, irritability Methylprednisolone Improved [7] encephalitis months Hu, Sensory Tactile and pain 1 month IVIG Not improved [8] 2 70 M Japan Atezolizumab SOX1 polyneuropathy disturbances 1.5 3 66 F China Sintilimab Hu Encephalitis Focal seizures Methylprednisolone Improved [9] months Numbness in hands and Sensory a few Methylprednisolone, 4 62 F USA Nivolumab Hu feet, tremor, loss of Not improved [10] polyneuropathy days IVIG dexterity, gait ataxia Limbic Short-term memory Methylprednisolone, Improved (not 5 71 F Switzerland Nivolumab + ipilimumab Hu 4 days [11] encephalitis deficits natalizumab completely) Sensory Painful paresthesia, gait 3 Methylprednisolone, Improved 6 46 M France Pembrolizumab Hu [12] neuropathy disturbance months IVIG (temporary) Dizziness, vomiting, 2 Improved (not 7 71 M France Atezolizumab Hu Encephalitis IVIG [12] diplopia, gait disturbance months completely) Present Limbic Disorientation, dysphagia, 2 Methylprednisolone, Improved (not 66 M Japan Atezolizumab Hu, Zic4 case encephalitis gait disturbance months IVIG completely) PNS, paraneoplastic neurological syndrome; ICI, immune checkpoint inhibitor; SCLC, small-cell lung cancer. Case Reports in Immunology 5 triggered by immune-checkpoint inhibitor treatment,” Jour- PNS induced by ICI in SCLC patients. Clinicians should nal of Neurology, vol. 267, no. 7, pp. 2154–2156, 2020. consider the possibility of PNS when patients with SCLC [13] F. Graus, F. Keime-Guibert, R. Reñe et al., “Anti-Hu-asso- develop neurological symptoms after ICI initiation. ciated paraneoplastic encephalomyelitis: analysis of 200 pa- tients,” Brain, vol. 124, no. 6, pp. 1138–1148, 2001. Conflicts of Interest [14] L. Bataller, D. F. Wade, F. Graus, H. D. Stacey, M. R. Rosenfeld, and J. Dalmau, “Antibodies to Zic4 in *e authors have no conflicts of interest directly relevant to paraneoplastic neurologic disorders and small-cell lung the content of this article to declare. cancer,” Neurology, vol. 62, no. 5, pp. 778–782, 2004. [15] Z. Hayden, B. Bon´ ´ e, G. Orsi et al., “Clinical characteristics and outcome of neuronal surface antibody-mediated autoimmune Acknowledgments encephalitis patients in a national cohort,” Frontiers in Neurology, vol. 12, Article ID 611597, 202. We would like to thank Editage (https://www.editage.com) [16] Y. Nakatani, N. Tanaka, T. Enami, S. Minami, T. Okazaki, and for providing English language editing assistance. K. Komuta, “Lambert-eaton myasthenic syndrome caused by nivolumab in a patient with squamous cell lung cancer,” Case Reports in Neurology, vol. 10, no. 3, pp. 346–352, 2018. References [17] K. Nakashima, Y. Fujii, M. Sato, K. Igarashi, M. Kobayashi, and T. Ishizuka, “A case of non-small cell lung cancer pre- [1] R. B. Darnell and J. B. Posner, “Paraneoplastic syndromes senting anti-amphiphysin antibody-positive paraneoplastic involving the nervous system,” New England Journal of neurological syndrome,” Respiratory Medicine Case Reports, Medicine, vol. 349, no. 16, pp. 1543–1554, 2003. vol. 34, Article ID 101525, 2021. [2] J. Dalmau and M. R. Rosenfeld, “Paraneoplastic syndromes of the CNS,” "e Lancet Neurology, vol. 7, no. 4, pp. 327–340, [3] L. Horn, A. S. Mansfield, A. Szcze˛sna et al., “First-line ate- zolizumab plus chemotherapy in extensive-stage small-cell lung cancer,” New England Journal of Medicine, vol. 379, no. 23, pp. 2220–2229, 2018. [4] M. A. Postow, R. Sidlow, and M. D. Hellmann, “Immune- related adverse events associated with immune checkpoint blockade,” New England Journal of Medicine, vol. 378, no. 2, pp. 158–168, 2018. [5] F. Graus and J. Dalmau, “Paraneoplastic neurological syn- dromes in the era of immune-checkpoint inhibitors,” Nature Reviews Clinical Oncology, vol. 16, no. 9, pp. 535–548, 2019. [6] A. Zekeridou and V. A. Lennon, “Neurologic autoimmunity in the era of checkpoint inhibitor cancer immunotherapy,” Mayo Clinic Proceedings, vol. 94, no. 9, pp. 1865–1878, 2019. [7] S. Tatsumi, K. Uryu, S. Iwasaki, and H. Harada, “A case of anti-CRMP5 paraneoplastic neurological syndrome induced by atezolizumab for small cell lung cancer,” Internal Medicine, (article in press), 2020. [8] T. Morimoto, T. Orihashi, K. Yamasaki, M. Tahara, K. Kato, and K. Yatera, “Paraneoplastic sensory polyneuropathy re- lated to anti-PD-L1-including anticancer treatment in a pa- tient with lung cancer,” Internal Medicine, vol. 60, no. 10, pp. 1577–1581, 2021. [9] K. Kang, K. Zheng, and Y. Zhang, “Paraneoplastic encephalitis and enteric neuropathy associated with anti-hu antibody in a patient following immune-checkpoint inhibitor therapy,” Journal of Immunotherapy (Hagerstown, Md: 1997), vol. 43, no. 5, pp. 165–168, 2020. [10] P. Raibagkar, D. Ho, K. S. Gunturu, and J. Srinivasan, “Worsening of anti-Hu paraneoplastic neurological syndrome related to anti-PD-1 treatment: case report and review of literature,” Journal of Neuroimmunology, vol. 341, Article ID 577184, 2020. [11] A. F. Hottinger, R. De Micheli, V. Guido, A. Karampera, P. Hagmann, and R. Du Pasquier, “Natalizumab may control immune checkpoint inhibitor-induced limbic encephalitis,” Neurology-Neuroimmunology Neuroinflammation, vol. 5, no. 2, p. e439, 2018. [12] N. Mongay-Ochoa, A. Vogrig, S. Muñiz-Castrillo, and J. Honnorat, “Anti-Hu-associated paraneoplastic syndromes

Journal

Case Reports in ImmunologyHindawi Publishing Corporation

Published: Jan 6, 2022

References