Inflammatory demyelinating polyneuropathy versus leptomeningeal disease following Ipilimumab
© The Author(s). 2018
Received: 7 July 2017
Accepted: 12 January 2018
Published: 30 January 2018
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.
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.
Ipilimumab immune-related toxicity presented as inflammatory demyelinating polyneuropathy, which was difficult to distinguish from leptomeningeal disease, a common complication of melanoma.
The frequency of leptomeningeal metastatic spread of melanoma in stage IV patients is 22–46% . Autoimmune neurologic events are a recognized complication of Ipilimumab therapy. Melanoma is associated with paraneoplastic neurologic syndromes. Determining the etiology of neurological complications in a patient with melanoma may thus present a challenge. It is important that the correct diagnosis is made because treatments are different and increasingly effective. We present a patient who developed inflammatory demyelinating polyneuropathy while taking Ipilimumab along with Vemurafenib for systemic disease, who was successfully treated with corticosteroids and discontinuation of Ipilimumab. Interestingly, he later developed clear leptomeningeal disease as part of his overall disease progression.
A 42 year old Caucasian male underwent wide local excision of a truncal 3.05 mm non-ulcerated melanoma with nevoid and spitzoid features. Sentinel node biopsy was negative. Two years later, a palpable left groin nodule was treated with superficial inguinal and deep pelvic lymphadenectomy followed by Interferon therapy. Interferon was tolerated poorly, with headaches and confusion, and stopped in the first month of therapy. Two and a half years later, PET/CT showed diffuse metastatic disease to the lungs, liver, right adrenal, and hilar lymph nodes. He was enrolled in a study evaluating 6 weeks of Vemurafenib followed by Ipilimumab 10 mg/kg (higher than the FDA approved dose of 3 mg/kg) intravenously every 3 weeks (NCT01673854) . After 6 weeks of Vemurafenib, tumors had shrunk by 9%. Ipilimumab was initiated 8 weeks after his first dose of Vemurafenib. After the second dose of Ipilimumab, he developed Grade 1 fatigue and began having intermittent mild headaches attributed to stress at work. MRI of the brain was negative.
Negative for malignant cells
6 month Follow-up
atypical cells with hyperchromatic nuclei and pigmentation, suspicious for melanoma
Borrelia burgdorferi antibody
Leishmania antibody IgG
Hepatitis B surface antigen
Hepatitis B surface antibody
Hepatitis B core antibody
Hepatitis C antibody
EBV nuclear antigen
EBV viral capsid antigen IgG
EBV viral capsid antigen IgM
Herpes 1 IgG
Herpes 2 IgG
NCS were normal in the upper extremities despite abnormal cervical spine MRI but showed multiple abnormalities in the lower extremities including absent sensory response in the right sural nerve, markedly slowed conduction velocities between the ankle and below the fibular head stimulation, severely reduced compound muscle action potential (CMAP) amplitudes, and mild-to-moderate prolongation of the distal latency on the left side. Left tibial nerve motor NCS showed significantly prolonged distal latency with moderately decreased CMAP amplitudes and slowed conduction velocity. Right tibial nerve motor NCS was normal except for a mild prolongation of distal latency and mildly slowed conduction velocity. The F-wave responses of the bilateral tibial nerves were absent, indicating a more proximal conduction block. Needle electromyography of the left lower extremity was significant for denervation changes in lumbar paraspinal and tibialis anterior muscle as well as neurogenic changes in all the tested muscles of the right leg. The study was indicative of an asymmetric, subacute to early chronic and ongoing lumbar polyradiculoneuropathy with axonal involvement and demyelinating features. It is not clear why the cervical and thoracic spine findings did not cause detectable signs nor symptoms.
Vemurafenib was restarted and Dexamethasone was continued. Patient had partial response systemically and neurologic improvement. Dexamethasone was tapered and then stopped almost 6 months after initiation. It is not possible to evaluate the extent to which the dexamethasone or anti-melanoma agents contributed to this outcome.
PET/CT 6.5 months after resuming Vemurafenib showed progression of disease. Brain MRI showed multiple new foci of nodular leptomeningeal enhancement consistent with metastases. CSF cytology was concerning for metastases (Table 1). Vemurafenib was discontinued, and intrathecal IL2 and Dabrafenib therapy was initiated at another institution. Head CT after 5 months of intrathecal IL2 showed progression with the disease now predominantly dura-based, and patient elected for home hospice.
Twenty-two to 46% of patients with stage IV melanoma have leptomeningeal involvement by the disease. Conversely, inflammatory demyelinating polyneuropathy presenting as paraneoplastic autoimmune disease associated with melanoma independent of immunotherapy is extremely rare, with only 10 cases reported in literature to date [3, 4], and maybe due to shared immunogenic ganglioside antigens  or to infectious and other agents associated with these neuropathies when they are seen in the absence of associated malignancy or immunotherapy. Case reports of sensorimotor neuropathy following Ipilimumab treatment [6–8] describe a variety of syndromes including CIDP , multifocal polyradiculoneuropathy , and meningo-radiculo-neuritis . The neurologic complications in our patient are consistent with those seen in patients who received Ipilimumab alone but have not to our knowledge been reported with Vemurafenib.
Patients with melanoma who develop neurologic complaints compatible with disease involving the spinal cord are most likely to have MRI of the spine as the first and frequently only diagnostic workup. Depending on the burden of metastatic disease, leptomeningeal carcinomatosis of the spine can have variable appearance. With mild disease, smooth, contiguous or noncontiguous fine coating of the cord surface and nerve roots, termed “sugar coating” or “zuckerguss” can be seen . Discrete nodules, large or small or even long segments of bulky mass-like disease can be seen in more severe disease. In either case, for the entity to cause diffuse, non-nodular involvement of cervical, thoracic and lumbar nerve roots, sparing the cord surface entirely, would be atypical for leptomeningeal carcinoma but very compatible with an inflammatory demyelinating polyneuropathy. The finding of non-nodular involvement of nerve roots without involvement of the cord in a patient receiving Ipilimumab or other immunomodulatory agents should prompt further evaluation for an immune based mechanism, especially since steroids or other therapies may significantly alter the course. Standard CSF studies across these cases, apart from negative cytology, have variable appearance, from normal to albuminocytologic dissociation to pleocytosis. They are not likely to be diagnostic beyond helping to rule out leptomeningeal carcinomatosis. Autoimmune workup in our patient was negative. The most helpful studies were NCS , as is usually the case in cases of inflammatory demyelinating polyneuropathy not associated with malignancy. Based on these findings, we would recommend that patients with cancer who were treated with immunotherapy and presenting with sensory and motor weakness for whom there is suspicion on MRI of an inflammatory demyelinating polyneuropathy, should undergo a thorough neurological evaluation which includes NCS, CSF studies, and consultation with a neurologist.
Leptomeningeal carcinomatosis and inflammatory demyelinating polyneuropathy, whether idiopathic or related to Ipilimumab or other immunomodulatory agents, may have similar clinical presentation, making it difficult to distinguish them. MRI is usually the initial study in patients presenting with signs/symptoms of spinal involvement. The finding of involvement of nerve roots, usually in a smooth, non-nodular fashion, with sparing of the surface of the cord should raise suspicion of an autoimmune, inflammatory process. Since immunomodulatory treatment may improve the course of this condition, more aggressive evaluation, such as NCS and CSF studies and evaluation by a neurologist are recommended. Inflammatory demyelinating polyneuropathies whether causally related to malignancy, immunotherapy, or not are complex and recommended treatments differ. Further studies in this area are clearly warranted.
Availability of data and materials
All data analyzed are included in this article and additional information is available upon request.
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 intellectual content. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable, not a clinical trial.
Consent for publication
Not required by our local IRB if patient is deceased.
DL participates in pharmaceutical trials sponsored by Bristol-Myers Squibb, the 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 competing interests.
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- Le Rhun E, Taillibert S, Chamberlain MC. Carcinomatous meningitis: Leptomeningeal metastases in solid tumors. Surg Neurol Int. 2013;4:S265–88.View ArticlePubMedPubMed CentralGoogle Scholar
- 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 followed by ipilimumab in patients with previously untreated BRAF-mutated metastatic melanoma. J Immunother Cancer. 2016;4:44.View ArticlePubMedPubMed CentralGoogle Scholar
- Chau AM, Yu A, Keezer MR. Chronic inflammatory demyelinating polyneuropathy and metastatic melanoma. Can J Neurol Sci. 2013;40:750–2.View ArticlePubMedGoogle Scholar
- Dbouk MB, Nafissi S, Ghorbani A. Chronic inflammatory demyelinating polyneuropathy following malignant melanoma. Neurosciences (Riyadh). 2012;17:167–70.Google Scholar
- Noronha AB, Harper JR, Ilyas AA, Reisfeld RA, Quarles RH. Myelin-associated glycoprotein shares an antigenic determinant with a glycoprotein of human melanoma cells. J Neurochem. 1986;47:1558–65.View ArticlePubMedGoogle Scholar
- Bompaire F, Mateus C, Taillia H, De Greslan T, Lahutte M, Sallansonnet-Froment M, Ouologuem M, Renard JL, Gorochov G, Robert C, Ricard D. Severe meningo-radiculo-neuritis associated with ipilimumab. Investig New Drugs. 2012;30:2407–10.View ArticleGoogle Scholar
- Liao B, Shroff S, Kamiya-Matsuoka C, Tummala S. Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma. Neuro-Oncology. 2014;16:589–93.View ArticlePubMedPubMed CentralGoogle Scholar
- Manousakis G, Koch J, Sommerville RB, El-Dokla A, Harms MB, Al-Lozi MT, Schmidt RE, Pestronk A. Multifocal radiculoneuropathy during ipilimumab treatment of melanoma. Muscle Nerve. 2013;48:440–4.View ArticlePubMedGoogle Scholar
- Kale HA, Sklar E. Magnetic resonance imaging findings in chronic inflammatory demyelinating polyneuropathy with intracranial findings and enhancing, thickened cranial and spinal nerves. Australas Radiol. 2007;51:B21–4.View ArticlePubMedGoogle Scholar
- Allen JA, Ney J, Lewis RA. Electrodiagnostic errors contribute to chronic inflammatory demyelinating polyneuropathy misdiagnosis. Muscle Nerve. 2017. [Epub ahead of print]. https://doi.org/10.1002/mus.25997.