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Inflammatory demyelinating polyneuropathy versus leptomeningeal disease following Ipilimumab

Inflammatory demyelinating polyneuropathy versus leptomeningeal disease following Ipilimumab Background: Ipilimumab is an FDA-approved anti-CTLA-4 monoclonal antibody used in treatment of metastatic melanoma. We present an unusual neurological complication of Ipilimumab therapy and the diagnostic dilemma it caused. Case presentation: A 42 year old male with Stage IV metastatic melanoma developed lower extremity weakness and sensory neuropathy following three doses of Ipilimumab. MRI of the lumbar spine was initially interpreted as diffuse leptomeningeal disease, and patient began Dexamethasone and radiation with improvement in symptoms. However, subsequent completion imaging revealed smooth nerve root involvement with sparing of the spinal cord, findings more compatible with inflammatory demyelinating polyneuropathy. The absence of malignant cells in the cerebrospinal fluid (CSF) and nerve conduction study (NCS) showing lumbar polyradiculoneuropathy with axonal involvement and demyelinating features supported the diagnosis of inflammatory demyelinating polyneuropathy. Later in the course of his disease, the patient developed frank leptomeningeal melanoma. Conclusion: Ipilimumab immune-related toxicity presented as inflammatory demyelinating polyneuropathy, which was difficult to distinguish from leptomeningeal disease, a common complication of melanoma. Keywords: Ipilimumab, Melanoma, Leptomeningeal carcinomatosis, Inflammatory demyelinating polyneuropathy, Autoimmune, Immunotherapy, Paraneoplastic autoimmune disease Background he later developed clear leptomeningeal disease as part of The frequency of leptomeningeal metastatic spread of his overall disease progression. melanoma in stage IV patients is 22–46% [1]. Auto- immune neurologic events are a recognized complication Case presentation of Ipilimumab therapy. Melanoma is associated with A 42 year old Caucasian male underwent wide local paraneoplastic neurologic syndromes. Determining the excision of a truncal 3.05 mm non-ulcerated melanoma etiology of neurological complications in a patient with with nevoid and spitzoid features. Sentinel node biopsy melanoma may thus present a challenge. It is important was negative. Two years later, a palpable left groin that the correct diagnosis is made because treatments are nodule was treated with superficial inguinal and deep different and increasingly effective. We present a patient pelvic lymphadenectomy followed by Interferon therapy. who developed inflammatory demyelinating polyneurop- Interferon was tolerated poorly, with headaches and athy while taking Ipilimumab along with Vemurafenib for confusion, and stopped in the first month of therapy. systemic disease, who was successfully treated with cortico- Two and a half years later, PET/CT showed diffuse meta- steroids and discontinuation of Ipilimumab. Interestingly, static disease to the lungs, liver, right adrenal, and hilar lymph nodes. He was enrolled in a study evaluating 6 weeks * Correspondence: lcafuir@emory.edu of Vemurafenib followed by Ipilimumab 10 mg/kg (higher Department of Hematology and Medical Oncology, Winship Cancer Institute than the FDA approved dose of 3 mg/kg) intravenously of Emory University, 1365C Clifton Road NE, Suite C5010, Atlanta, GA 30322, every 3 weeks (NCT01673854) [2]. After 6 weeks of USA Full list of author information is available at the end of the article Vemurafenib, tumors had shrunk by 9%. Ipilimumab was © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Cafuir et al. Journal for ImmunoTherapy of Cancer (2018) 6:11 Page 2 of 5 initiated 8 weeks after his first dose of Vemurafenib. After extremity signs nor symptoms. Vemurafenib was held, the second dose of Ipilimumab, he developed Grade 1 dexamethasone was started, and daily radiation was initi- fatigue and began having intermittent mild headaches ated to conus and cauda equina at 3 Gy per fraction for attributed to stress at work. MRI of the brain was negative. presumed leptomeningeal disease. However, completion Six days following the third dose of Ipilimumab, he MRI of the spine done after 5 days of radiation, and presented with bilateral hip pain 8 on a 10 point scale, 16 days after the initial MRI of the lumbar spine, revealed subjective bilateral thigh weakness, and paresthesia of diffuse, symmetric, and smooth nerve root enhancement the soles of his feet. Initial examination showed normal affecting the entire spine while sparing the entirety of the muscle strength except for the left quadriceps (4/5). cord surface; imaging findings more compatible with Upper extremity strength was intact. Sensory exam was inflammatory demyelinating polyneuropathy (Fig. 2). Brain not performed. MRI of the lumbar spine demonstrated MRI was normal. Radiation was stopped, neurology was diffuse enhancement surrounding the entire conus and all consulted, and workup for inflammatory demyelinating of the nerve roots thought most compatible with lepto- polyneuropathy was initiated. CSF was negative for meningeal carcinomatosis (Fig. 1). The remainder of the malignant cells, but showed significantly increased protein spine was not imaged because of the patient’spainand without pleocytosis (Table 1). Autoimmune testing was absence of signs/symptoms suggestive of involvement unremarkable (Table 1). Electrophysiological studies were above the lumbar spine. PET/CT performed the following done 8 weeks after the onset of the first neurological day showed 23% increase in extra-CNS tumor measure- complaints, and at that point, his neurological exam ments. Vemurafenib was resumed because of worsening showed weakness in foot dorsiflexion, knee and hip of disease on Ipilimumab and previous improvement, flexion bilaterally, worse on the left. He had impaired although slight, on Vemurafenib for 6 weeks. vibration in the toes and absent delayed tendon reflexes in Patient’s lower extremity weakness, pain, and numbness the lower extremities. worsened rapidly over the next week with deterioration to NCS were normal in the upper extremities despite ECOG 3. There were still no cranial nerve nor upper abnormal cervical spine MRI but showed multiple Fig. 1 Initial MRI lumbar spine following Ipilimumab. Sagittal and axial T1w fat (left and top right) saturated post contrast and axial T2w FSE (bottom right) images demonstrating smooth, non-nodular avid enhancement of cauda equina without significant nerve root thickening Cafuir et al. Journal for ImmunoTherapy of Cancer (2018) 6:11 Page 3 of 5 Fig. 2 Follow up post contrast cervical spine MRI. Parasagittal and axial T1w fat saturated post contrast images demonstrating smooth avid enhancement of all anterior and posterior cervical nerve roots (arrows) but no involvement of the cord surface. Both factors strongly mitigate against leptomeningeal metastatic disease abnormalities in the lower extremities including absent Vemurafenib was restarted and Dexamethasone was con- sensory response in the right sural nerve, markedly slowed tinued. Patient had partial response systemically and neuro- conduction velocities between the ankle and below the logic improvement. Dexamethasone was tapered and then fibular head stimulation, severely reduced compound stopped almost 6 months after initiation. It is not possible muscle action potential (CMAP) amplitudes, and mild-to- to evaluate the extent to which the dexamethasone or anti- moderate prolongation of the distal latency on the left melanoma agents contributed to this outcome. side. Left tibial nerve motor NCS showed significantly PET/CT 6.5 months after resuming Vemurafenib showed prolonged distal latency with moderately decreased progression of disease. Brain MRI showed multiple new foci CMAP amplitudes and slowed conduction velocity. Right of nodular leptomeningeal enhancement consistent with tibial nerve motor NCS was normal except for a mild metastases. CSF cytology was concerning for metastases prolongation of distal latency and mildly slowed conduc- (Table 1). Vemurafenib was discontinued, and intrathecal tion velocity. The F-wave responses of the bilateral tibial IL2 and Dabrafenib therapy was initiated at another institu- nerves were absent, indicating a more proximal conduc- tion. Head CT after 5 months of intrathecal IL2 showed tion block. Needle electromyography of the left lower progression with the disease now predominantly dura- extremity was significant for denervation changes in based, and patient elected for home hospice. lumbar paraspinal and tibialis anterior muscle as well as neurogenic changes in all the tested muscles of the right Discussion leg. The study was indicative of an asymmetric, subacute to Twenty-two to 46% of patients with stage IV melanoma early chronic and ongoing lumbar polyradiculoneuropathy have leptomeningeal involvement by the disease. Con- with axonal involvement and demyelinating features. It is versely, inflammatory demyelinating polyneuropathy not clear why the cervical and thoracic spine findings did presenting as paraneoplastic autoimmune disease associ- not cause detectable signs nor symptoms. ated with melanoma independent of immunotherapy is Cafuir et al. Journal for ImmunoTherapy of Cancer (2018) 6:11 Page 4 of 5 Table 1 Neuro-oncology evaluation Table 1 Neuro-oncology evaluation (Continued) Laboratory test Value Normal Units Laboratory test Value Normal Units Blood HIV Negative TSH 2.11 0.55–4.78 mcIU/mL Herpes 1 IgG Negative CK 91 49–397 Unit/L Herpes 2 IgG Negative WBC 11.7 4.2–9.1 K/uL Abbreviations: TSH thyroid stimulating hormone, CK creatinine kinase, WBC white blood cell, RBC red blood cell, GM monosialoganglioside, GD Vitamin B12 587 211–911 Pg/mL disialoganglioside, GQ tetrasialoganglioside, ENA extractable nuclear antigen screen, ANCA anti-neutrophil cytoplasmic antibody, dsDNA double stranded CSF DNA, AMA Mitochondrial M2 antibody IgG, CMV Cytomegalovirus, EBV Initial Epstein-Barr virus, HIV human immunodeficiency virus, IV index value, LIV Lyme index value WBC 1 0–5 Cells/uL Hepatitis B surface antibody < 8 mIU/mL indicates inadequate antibody response to vaccination RBC 0 0 Cells/uL Protein > 300 15–45 Mg/dL Glucose 73 40–70 Mg/dL extremely rare, with only 10 cases reported in literature Cytology Negative for malignant to date [3, 4], and maybe due to shared immunogenic cells ganglioside antigens [5] or to infectious and other agents 6 month Follow-up associated with these neuropathies when they are seen WBC 3 0–5 Cells/uL in the absence of associated malignancy or immunother- RBC 6 0 Cells/uL apy. Case reports of sensorimotor neuropathy following Protein 169 15–45 Mg/dL Ipilimumab treatment [6–8] describe a variety of syn- Glucose 56 40–70 Mg/dL dromes including CIDP [7], multifocal polyradiculo- neuropathy [8], and meningo-radiculo-neuritis [6]. The Cytology atypical cells with hyperchromatic neurologic complications in our patient are consistent nuclei and pigmentation, with those seen in patients who received Ipilimumab suspicious for melanoma alone but have not to our knowledge been reported with Autoimmune Studies Vemurafenib. Asialo-GM1 (IgG/IgM) 13 0–50 IV Patients with melanoma who develop neurologic com- GM2 (IgG/IgM) 4 0–50 IV plaints compatible with disease involving the spinal cord GD1a (IgG/IgM) 8 0–50 IV are most likely to have MRI of the spine as the first and GD1b (IgG/IgM) 4 0–50 IV frequently only diagnostic workup. Depending on the GQ1b (IgG/IgM) 5 0–50 IV burden of metastatic disease, leptomeningeal carcinoma- GM-1 (IgG) 3 0–50 IV tosis of the spine can have variable appearance. With GM-1 (IgM) 5 0–50 IV mild disease, smooth, contiguous or noncontiguous fine AMA 1.5 0–20 Units coating of the cord surface and nerve roots, termed Rheumatoid Factor < 20 < 20 IU/mL “sugar coating” or “zuckerguss” can be seen [9]. Discrete ANCA < 1:20 < 1:20 nodules, large or small or even long segments of bulky mass-like disease can be seen in more severe disease. In dsDNA antibody Negative either case, for the entity to cause diffuse, non-nodular ENA Negative involvement of cervical, thoracic and lumbar nerve Borrelia burgdorferi 0.20 0–1.20 LIV antibody roots, sparing the cord surface entirely, would be atyp- Leishmania antibody IgG 0 0 units ical for leptomeningeal carcinoma but very compatible with an inflammatory demyelinating polyneuropathy. Hepatitis panel The finding of non-nodular involvement of nerve Hepatitis B surface antigen Negative a roots without involvement of the cord in a patient Hepatitis B surface antibody 0.04 mIU/mL receiving Ipilimumab or other immunomodulatory Hepatitis B core antibody Negative agents should prompt further evaluation for an Hepatitis C antibody Negative immune based mechanism, especially since steroids or Viral studies other therapies may significantly alter the course. CMV antibody Positive Standard CSF studies across these cases, apart from EBV nuclear antigen Positive negative cytology, have variable appearance, from EBV viral capsid antigen IgG Positive normal to albuminocytologic dissociation to pleocyto- EBV viral capsid antigen Negative sis. They are not likely to be diagnostic beyond help- IgM ing to rule out leptomeningeal carcinomatosis. Autoimmune workup in our patient was negative. Cafuir et al. Journal for ImmunoTherapy of Cancer (2018) 6:11 Page 5 of 5 The most helpful studies were NCS [10], as is usually Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in the case in cases of inflammatory demyelinating poly- published maps and institutional affiliations. neuropathy not associated with malignancy. Based on these findings, we would recommend that patients Author details Department of Hematology and Medical Oncology, Winship Cancer Institute with cancer who were treated with immunotherapy of Emory University, 1365C Clifton Road NE, Suite C5010, Atlanta, GA 30322, and presenting with sensory and motor weakness for 2 USA. Department of Radiology, Baylor College of Medicine, 6701 Fannin whom there is suspicion on MRI of an inflammatory Street, Suite 470, Houston, TX 77030, USA. Department of Neurology, Emory University School of Medicine, 12 Executive Park Drive NE, Atlanta, GA 30329, demyelinating polyneuropathy, should undergo a thor- USA. ough neurological evaluation which includes NCS, CSF studies, and consultation with a neurologist. Received: 7 July 2017 Accepted: 12 January 2018 References Conclusion 1. Le Rhun E, Taillibert S, Chamberlain MC. Carcinomatous meningitis: Leptomeningeal carcinomatosis and inflammatory de- Leptomeningeal metastases in solid tumors. Surg Neurol Int. 2013;4:S265–88. myelinating polyneuropathy, whether idiopathic or re- 2. Amin A, Lawson DH, Salama AK, Koon HB, Guthrie T Jr, Thomas SS, O'Day SJ, Shaheen MF, Zhang B, Francis S, Hodi FS. Phase II study of vemurafenib lated to Ipilimumab or other immunomodulatory agents, followed by ipilimumab in patients with previously untreated BRAF-mutated may have similar clinical presentation, making it difficult metastatic melanoma. J Immunother Cancer. 2016;4:44. to distinguish them. MRI is usually the initial study in 3. Chau AM, Yu A, Keezer MR. Chronic inflammatory demyelinating polyneuropathy and metastatic melanoma. Can J Neurol Sci. 2013;40:750–2. patients presenting with signs/symptoms of spinal in- 4. Dbouk MB, Nafissi S, Ghorbani A. Chronic inflammatory demyelinating volvement. The finding of involvement of nerve roots, polyneuropathy following malignant melanoma. Neurosciences (Riyadh). usually in a smooth, non-nodular fashion, with sparing 2012;17:167–70. 5. Noronha AB, Harper JR, Ilyas AA, Reisfeld RA, Quarles RH. Myelin-associated of the surface of the cord should raise suspicion of an glycoprotein shares an antigenic determinant with a glycoprotein of human autoimmune, inflammatory process. Since immunomod- melanoma cells. J Neurochem. 1986;47:1558–65. ulatory treatment may improve the course of this condi- 6. Bompaire F, Mateus C, Taillia H, De Greslan T, Lahutte M, Sallansonnet- Froment M, Ouologuem M, Renard JL, Gorochov G, Robert C, Ricard D. tion, more aggressive evaluation, such as NCS and CSF Severe meningo-radiculo-neuritis associated with ipilimumab. Investig New studies and evaluation by a neurologist are recom- Drugs. 2012;30:2407–10. mended. Inflammatory demyelinating polyneuropathies 7. Liao B, Shroff S, Kamiya-Matsuoka C, Tummala S. Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma. whether causally related to malignancy, immunotherapy, Neuro-Oncology. 2014;16:589–93. or not are complex and recommended treatments differ. 8. Manousakis G, Koch J, Sommerville RB, El-Dokla A, Harms MB, Al-Lozi MT, Further studies in this area are clearly warranted. Schmidt RE, Pestronk A. Multifocal radiculoneuropathy during ipilimumab treatment of melanoma. Muscle Nerve. 2013;48:440–4. 9. Kale HA, Sklar E. Magnetic resonance imaging findings in chronic Acknowledgements inflammatory demyelinating polyneuropathy with intracranial findings Not applicable. and enhancing, thickened cranial and spinal nerves. Australas Radiol. 2007;51:B21–4. Funding 10. Allen JA, Ney J, Lewis RA. Electrodiagnostic errors contribute to chronic Not applicable. inflammatory demyelinating polyneuropathy misdiagnosis. Muscle Nerve. 2017. [Epub ahead of print]. https://doi.org/10.1002/mus.25997. Availability of data and materials All data analyzed are included in this article and additional information is available upon request. Authors’ contributions LC drafted and revised the manuscript for intellectual content. DL treated the patient, conceptualized this case report and helped revise the manuscript. ND provided the images and their interpretation and wrote a section of the manuscript. VK provided the nerve conduction study data and its interpretation. AV consulted in the care of the patient, helped revise the manuscript for Submit your next manuscript to BioMed Central intellectual content. All authors read and approved the final manuscript. and we will help you at every step: Ethics approval and consent to participate • We accept pre-submission inquiries Not applicable, not a clinical trial. � Our selector tool helps you to find the most relevant journal � We provide round the clock customer support Consent for publication Not required by our local IRB if patient is deceased. � Convenient online submission � Thorough peer review Competing interests � Inclusion in PubMed and all major indexing services DL participates in pharmaceutical trials sponsored by Bristol-Myers Squibb, the � Maximum visibility for your research maker of Ipilimumab. VK is the Principal Investigator for the NN103 Myasthenia Gravis Study funded by the NIH. LC, ND, and AV declare that they have no Submit your manuscript at competing interests. www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal for ImmunoTherapy of Cancer Springer Journals

Inflammatory demyelinating polyneuropathy versus leptomeningeal disease following Ipilimumab

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Springer Journals
Copyright
Copyright © 2018 by The Author(s).
Subject
Medicine & Public Health; Oncology; Immunology
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2051-1426
DOI
10.1186/s40425-018-0318-x
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Abstract

Background: Ipilimumab is an FDA-approved anti-CTLA-4 monoclonal antibody used in treatment of metastatic melanoma. We present an unusual neurological complication of Ipilimumab therapy and the diagnostic dilemma it caused. Case presentation: A 42 year old male with Stage IV metastatic melanoma developed lower extremity weakness and sensory neuropathy following three doses of Ipilimumab. MRI of the lumbar spine was initially interpreted as diffuse leptomeningeal disease, and patient began Dexamethasone and radiation with improvement in symptoms. However, subsequent completion imaging revealed smooth nerve root involvement with sparing of the spinal cord, findings more compatible with inflammatory demyelinating polyneuropathy. The absence of malignant cells in the cerebrospinal fluid (CSF) and nerve conduction study (NCS) showing lumbar polyradiculoneuropathy with axonal involvement and demyelinating features supported the diagnosis of inflammatory demyelinating polyneuropathy. Later in the course of his disease, the patient developed frank leptomeningeal melanoma. Conclusion: Ipilimumab immune-related toxicity presented as inflammatory demyelinating polyneuropathy, which was difficult to distinguish from leptomeningeal disease, a common complication of melanoma. Keywords: Ipilimumab, Melanoma, Leptomeningeal carcinomatosis, Inflammatory demyelinating polyneuropathy, Autoimmune, Immunotherapy, Paraneoplastic autoimmune disease Background he later developed clear leptomeningeal disease as part of The frequency of leptomeningeal metastatic spread of his overall disease progression. melanoma in stage IV patients is 22–46% [1]. Auto- immune neurologic events are a recognized complication Case presentation of Ipilimumab therapy. Melanoma is associated with A 42 year old Caucasian male underwent wide local paraneoplastic neurologic syndromes. Determining the excision of a truncal 3.05 mm non-ulcerated melanoma etiology of neurological complications in a patient with with nevoid and spitzoid features. Sentinel node biopsy melanoma may thus present a challenge. It is important was negative. Two years later, a palpable left groin that the correct diagnosis is made because treatments are nodule was treated with superficial inguinal and deep different and increasingly effective. We present a patient pelvic lymphadenectomy followed by Interferon therapy. who developed inflammatory demyelinating polyneurop- Interferon was tolerated poorly, with headaches and athy while taking Ipilimumab along with Vemurafenib for confusion, and stopped in the first month of therapy. systemic disease, who was successfully treated with cortico- Two and a half years later, PET/CT showed diffuse meta- steroids and discontinuation of Ipilimumab. Interestingly, static disease to the lungs, liver, right adrenal, and hilar lymph nodes. He was enrolled in a study evaluating 6 weeks * Correspondence: lcafuir@emory.edu of Vemurafenib followed by Ipilimumab 10 mg/kg (higher Department of Hematology and Medical Oncology, Winship Cancer Institute than the FDA approved dose of 3 mg/kg) intravenously of Emory University, 1365C Clifton Road NE, Suite C5010, Atlanta, GA 30322, every 3 weeks (NCT01673854) [2]. After 6 weeks of USA Full list of author information is available at the end of the article Vemurafenib, tumors had shrunk by 9%. Ipilimumab was © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Cafuir et al. Journal for ImmunoTherapy of Cancer (2018) 6:11 Page 2 of 5 initiated 8 weeks after his first dose of Vemurafenib. After extremity signs nor symptoms. Vemurafenib was held, the second dose of Ipilimumab, he developed Grade 1 dexamethasone was started, and daily radiation was initi- fatigue and began having intermittent mild headaches ated to conus and cauda equina at 3 Gy per fraction for attributed to stress at work. MRI of the brain was negative. presumed leptomeningeal disease. However, completion Six days following the third dose of Ipilimumab, he MRI of the spine done after 5 days of radiation, and presented with bilateral hip pain 8 on a 10 point scale, 16 days after the initial MRI of the lumbar spine, revealed subjective bilateral thigh weakness, and paresthesia of diffuse, symmetric, and smooth nerve root enhancement the soles of his feet. Initial examination showed normal affecting the entire spine while sparing the entirety of the muscle strength except for the left quadriceps (4/5). cord surface; imaging findings more compatible with Upper extremity strength was intact. Sensory exam was inflammatory demyelinating polyneuropathy (Fig. 2). Brain not performed. MRI of the lumbar spine demonstrated MRI was normal. Radiation was stopped, neurology was diffuse enhancement surrounding the entire conus and all consulted, and workup for inflammatory demyelinating of the nerve roots thought most compatible with lepto- polyneuropathy was initiated. CSF was negative for meningeal carcinomatosis (Fig. 1). The remainder of the malignant cells, but showed significantly increased protein spine was not imaged because of the patient’spainand without pleocytosis (Table 1). Autoimmune testing was absence of signs/symptoms suggestive of involvement unremarkable (Table 1). Electrophysiological studies were above the lumbar spine. PET/CT performed the following done 8 weeks after the onset of the first neurological day showed 23% increase in extra-CNS tumor measure- complaints, and at that point, his neurological exam ments. Vemurafenib was resumed because of worsening showed weakness in foot dorsiflexion, knee and hip of disease on Ipilimumab and previous improvement, flexion bilaterally, worse on the left. He had impaired although slight, on Vemurafenib for 6 weeks. vibration in the toes and absent delayed tendon reflexes in Patient’s lower extremity weakness, pain, and numbness the lower extremities. worsened rapidly over the next week with deterioration to NCS were normal in the upper extremities despite ECOG 3. There were still no cranial nerve nor upper abnormal cervical spine MRI but showed multiple Fig. 1 Initial MRI lumbar spine following Ipilimumab. Sagittal and axial T1w fat (left and top right) saturated post contrast and axial T2w FSE (bottom right) images demonstrating smooth, non-nodular avid enhancement of cauda equina without significant nerve root thickening Cafuir et al. Journal for ImmunoTherapy of Cancer (2018) 6:11 Page 3 of 5 Fig. 2 Follow up post contrast cervical spine MRI. Parasagittal and axial T1w fat saturated post contrast images demonstrating smooth avid enhancement of all anterior and posterior cervical nerve roots (arrows) but no involvement of the cord surface. Both factors strongly mitigate against leptomeningeal metastatic disease abnormalities in the lower extremities including absent Vemurafenib was restarted and Dexamethasone was con- sensory response in the right sural nerve, markedly slowed tinued. Patient had partial response systemically and neuro- conduction velocities between the ankle and below the logic improvement. Dexamethasone was tapered and then fibular head stimulation, severely reduced compound stopped almost 6 months after initiation. It is not possible muscle action potential (CMAP) amplitudes, and mild-to- to evaluate the extent to which the dexamethasone or anti- moderate prolongation of the distal latency on the left melanoma agents contributed to this outcome. side. Left tibial nerve motor NCS showed significantly PET/CT 6.5 months after resuming Vemurafenib showed prolonged distal latency with moderately decreased progression of disease. Brain MRI showed multiple new foci CMAP amplitudes and slowed conduction velocity. Right of nodular leptomeningeal enhancement consistent with tibial nerve motor NCS was normal except for a mild metastases. CSF cytology was concerning for metastases prolongation of distal latency and mildly slowed conduc- (Table 1). Vemurafenib was discontinued, and intrathecal tion velocity. The F-wave responses of the bilateral tibial IL2 and Dabrafenib therapy was initiated at another institu- nerves were absent, indicating a more proximal conduc- tion. Head CT after 5 months of intrathecal IL2 showed tion block. Needle electromyography of the left lower progression with the disease now predominantly dura- extremity was significant for denervation changes in based, and patient elected for home hospice. lumbar paraspinal and tibialis anterior muscle as well as neurogenic changes in all the tested muscles of the right Discussion leg. The study was indicative of an asymmetric, subacute to Twenty-two to 46% of patients with stage IV melanoma early chronic and ongoing lumbar polyradiculoneuropathy have leptomeningeal involvement by the disease. Con- with axonal involvement and demyelinating features. It is versely, inflammatory demyelinating polyneuropathy not clear why the cervical and thoracic spine findings did presenting as paraneoplastic autoimmune disease associ- not cause detectable signs nor symptoms. ated with melanoma independent of immunotherapy is Cafuir et al. Journal for ImmunoTherapy of Cancer (2018) 6:11 Page 4 of 5 Table 1 Neuro-oncology evaluation Table 1 Neuro-oncology evaluation (Continued) Laboratory test Value Normal Units Laboratory test Value Normal Units Blood HIV Negative TSH 2.11 0.55–4.78 mcIU/mL Herpes 1 IgG Negative CK 91 49–397 Unit/L Herpes 2 IgG Negative WBC 11.7 4.2–9.1 K/uL Abbreviations: TSH thyroid stimulating hormone, CK creatinine kinase, WBC white blood cell, RBC red blood cell, GM monosialoganglioside, GD Vitamin B12 587 211–911 Pg/mL disialoganglioside, GQ tetrasialoganglioside, ENA extractable nuclear antigen screen, ANCA anti-neutrophil cytoplasmic antibody, dsDNA double stranded CSF DNA, AMA Mitochondrial M2 antibody IgG, CMV Cytomegalovirus, EBV Initial Epstein-Barr virus, HIV human immunodeficiency virus, IV index value, LIV Lyme index value WBC 1 0–5 Cells/uL Hepatitis B surface antibody < 8 mIU/mL indicates inadequate antibody response to vaccination RBC 0 0 Cells/uL Protein > 300 15–45 Mg/dL Glucose 73 40–70 Mg/dL extremely rare, with only 10 cases reported in literature Cytology Negative for malignant to date [3, 4], and maybe due to shared immunogenic cells ganglioside antigens [5] or to infectious and other agents 6 month Follow-up associated with these neuropathies when they are seen WBC 3 0–5 Cells/uL in the absence of associated malignancy or immunother- RBC 6 0 Cells/uL apy. Case reports of sensorimotor neuropathy following Protein 169 15–45 Mg/dL Ipilimumab treatment [6–8] describe a variety of syn- Glucose 56 40–70 Mg/dL dromes including CIDP [7], multifocal polyradiculo- neuropathy [8], and meningo-radiculo-neuritis [6]. The Cytology atypical cells with hyperchromatic neurologic complications in our patient are consistent nuclei and pigmentation, with those seen in patients who received Ipilimumab suspicious for melanoma alone but have not to our knowledge been reported with Autoimmune Studies Vemurafenib. Asialo-GM1 (IgG/IgM) 13 0–50 IV Patients with melanoma who develop neurologic com- GM2 (IgG/IgM) 4 0–50 IV plaints compatible with disease involving the spinal cord GD1a (IgG/IgM) 8 0–50 IV are most likely to have MRI of the spine as the first and GD1b (IgG/IgM) 4 0–50 IV frequently only diagnostic workup. Depending on the GQ1b (IgG/IgM) 5 0–50 IV burden of metastatic disease, leptomeningeal carcinoma- GM-1 (IgG) 3 0–50 IV tosis of the spine can have variable appearance. With GM-1 (IgM) 5 0–50 IV mild disease, smooth, contiguous or noncontiguous fine AMA 1.5 0–20 Units coating of the cord surface and nerve roots, termed Rheumatoid Factor < 20 < 20 IU/mL “sugar coating” or “zuckerguss” can be seen [9]. Discrete ANCA < 1:20 < 1:20 nodules, large or small or even long segments of bulky mass-like disease can be seen in more severe disease. In dsDNA antibody Negative either case, for the entity to cause diffuse, non-nodular ENA Negative involvement of cervical, thoracic and lumbar nerve Borrelia burgdorferi 0.20 0–1.20 LIV antibody roots, sparing the cord surface entirely, would be atyp- Leishmania antibody IgG 0 0 units ical for leptomeningeal carcinoma but very compatible with an inflammatory demyelinating polyneuropathy. Hepatitis panel The finding of non-nodular involvement of nerve Hepatitis B surface antigen Negative a roots without involvement of the cord in a patient Hepatitis B surface antibody 0.04 mIU/mL receiving Ipilimumab or other immunomodulatory Hepatitis B core antibody Negative agents should prompt further evaluation for an Hepatitis C antibody Negative immune based mechanism, especially since steroids or Viral studies other therapies may significantly alter the course. CMV antibody Positive Standard CSF studies across these cases, apart from EBV nuclear antigen Positive negative cytology, have variable appearance, from EBV viral capsid antigen IgG Positive normal to albuminocytologic dissociation to pleocyto- EBV viral capsid antigen Negative sis. They are not likely to be diagnostic beyond help- IgM ing to rule out leptomeningeal carcinomatosis. Autoimmune workup in our patient was negative. Cafuir et al. Journal for ImmunoTherapy of Cancer (2018) 6:11 Page 5 of 5 The most helpful studies were NCS [10], as is usually Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in the case in cases of inflammatory demyelinating poly- published maps and institutional affiliations. neuropathy not associated with malignancy. Based on these findings, we would recommend that patients Author details Department of Hematology and Medical Oncology, Winship Cancer Institute with cancer who were treated with immunotherapy of Emory University, 1365C Clifton Road NE, Suite C5010, Atlanta, GA 30322, and presenting with sensory and motor weakness for 2 USA. Department of Radiology, Baylor College of Medicine, 6701 Fannin whom there is suspicion on MRI of an inflammatory Street, Suite 470, Houston, TX 77030, USA. Department of Neurology, Emory University School of Medicine, 12 Executive Park Drive NE, Atlanta, GA 30329, demyelinating polyneuropathy, should undergo a thor- USA. ough neurological evaluation which includes NCS, CSF studies, and consultation with a neurologist. Received: 7 July 2017 Accepted: 12 January 2018 References Conclusion 1. Le Rhun E, Taillibert S, Chamberlain MC. Carcinomatous meningitis: Leptomeningeal carcinomatosis and inflammatory de- Leptomeningeal metastases in solid tumors. Surg Neurol Int. 2013;4:S265–88. myelinating polyneuropathy, whether idiopathic or re- 2. Amin A, Lawson DH, Salama AK, Koon HB, Guthrie T Jr, Thomas SS, O'Day SJ, Shaheen MF, Zhang B, Francis S, Hodi FS. Phase II study of vemurafenib lated to Ipilimumab or other immunomodulatory agents, followed by ipilimumab in patients with previously untreated BRAF-mutated may have similar clinical presentation, making it difficult metastatic melanoma. J Immunother Cancer. 2016;4:44. to distinguish them. MRI is usually the initial study in 3. Chau AM, Yu A, Keezer MR. Chronic inflammatory demyelinating polyneuropathy and metastatic melanoma. Can J Neurol Sci. 2013;40:750–2. patients presenting with signs/symptoms of spinal in- 4. Dbouk MB, Nafissi S, Ghorbani A. Chronic inflammatory demyelinating volvement. The finding of involvement of nerve roots, polyneuropathy following malignant melanoma. Neurosciences (Riyadh). usually in a smooth, non-nodular fashion, with sparing 2012;17:167–70. 5. Noronha AB, Harper JR, Ilyas AA, Reisfeld RA, Quarles RH. Myelin-associated of the surface of the cord should raise suspicion of an glycoprotein shares an antigenic determinant with a glycoprotein of human autoimmune, inflammatory process. Since immunomod- melanoma cells. J Neurochem. 1986;47:1558–65. ulatory treatment may improve the course of this condi- 6. Bompaire F, Mateus C, Taillia H, De Greslan T, Lahutte M, Sallansonnet- Froment M, Ouologuem M, Renard JL, Gorochov G, Robert C, Ricard D. tion, more aggressive evaluation, such as NCS and CSF Severe meningo-radiculo-neuritis associated with ipilimumab. Investig New studies and evaluation by a neurologist are recom- Drugs. 2012;30:2407–10. mended. Inflammatory demyelinating polyneuropathies 7. Liao B, Shroff S, Kamiya-Matsuoka C, Tummala S. Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma. whether causally related to malignancy, immunotherapy, Neuro-Oncology. 2014;16:589–93. or not are complex and recommended treatments differ. 8. Manousakis G, Koch J, Sommerville RB, El-Dokla A, Harms MB, Al-Lozi MT, Further studies in this area are clearly warranted. Schmidt RE, Pestronk A. Multifocal radiculoneuropathy during ipilimumab treatment of melanoma. Muscle Nerve. 2013;48:440–4. 9. Kale HA, Sklar E. Magnetic resonance imaging findings in chronic Acknowledgements inflammatory demyelinating polyneuropathy with intracranial findings Not applicable. and enhancing, thickened cranial and spinal nerves. Australas Radiol. 2007;51:B21–4. Funding 10. Allen JA, Ney J, Lewis RA. Electrodiagnostic errors contribute to chronic Not applicable. inflammatory demyelinating polyneuropathy misdiagnosis. Muscle Nerve. 2017. [Epub ahead of print]. https://doi.org/10.1002/mus.25997. Availability of data and materials All data analyzed are included in this article and additional information is available upon request. Authors’ contributions LC drafted and revised the manuscript for intellectual content. DL treated the patient, conceptualized this case report and helped revise the manuscript. ND provided the images and their interpretation and wrote a section of the manuscript. VK provided the nerve conduction study data and its interpretation. AV consulted in the care of the patient, helped revise the manuscript for Submit your next manuscript to BioMed Central intellectual content. All authors read and approved the final manuscript. and we will help you at every step: Ethics approval and consent to participate • We accept pre-submission inquiries Not applicable, not a clinical trial. � Our selector tool helps you to find the most relevant journal � We provide round the clock customer support Consent for publication Not required by our local IRB if patient is deceased. � Convenient online submission � Thorough peer review Competing interests � Inclusion in PubMed and all major indexing services DL participates in pharmaceutical trials sponsored by Bristol-Myers Squibb, the � Maximum visibility for your research maker of Ipilimumab. VK is the Principal Investigator for the NN103 Myasthenia Gravis Study funded by the NIH. 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