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I have included both case reports that need to be used for the above abstract. Please utilize pumbmed, NEJM, and uptodate to gather information and use in this abstract)
Template for ACP follow the outline below using information provided
Title: Pembrolizumab-Induced Acute Inflammatory Demyelinating Polyneuropathy
Authors: Rupesh Manam MD, Josh Gross MD, Jasmine Martin MD, Dhishna Chaudhary MD, Patricio S. Espinosa MD, Sajeel Chowdhary MD and Edgardo Santos MD
Introduction: Pembrolizumab, is a monoclonal antibody against immune checkpoint programmed death receptor (PD-1) that facilitates apoptosis of cells expressing PD-1. It is FDA approved for treatment of a growing number of oncologic conditions. Reported immunological related adverse events include pneumonitis, colitis, hepatitis, nephritis, and endocrinopathies. Neurological related adverse events are less understood and have been infrequently cited in medical literature. We herein present 2 cases of acute inflammatory demyelinating polyneuropathy (AIDP) as a rare complication of pembrolizumab.
Case Presentation: 73-year-old White male with history of stage IV poorly differentiated lung adenocarcinoma with PD-L1 of 20% was started on carboplatin with pemetrexed plus pembrolizumab. Three-weeks after initiating treatment with pembrolizumab patient developed ascending generalized motor weakness requiring hospital admission. Motor strength was 3/5 bilateral(B/L) upper extremities (UE) and lower extremities (LE) with absent deep tendon reflexes. Lumbar puncture(LP) revealed albuminocytological dissociation in the CSF (68). Intravenous(IV) steroids and intravenous immunoglobulin (IVIG) were initiated. Despite five IVIG infusions, the patient’s motor strength diminished to 2/5 in bilateral UE and LE, negative inspiratory force was -20 and forced vital capacity was 1.1 prompting intensive care unit monitoring. IVIG was discontinued, and patient was started on plasmapheresis; patient received 8 sessions of plasmapheresis as well as steroids at high-dose. After 25 days of hospitalization, patient showed clinical improvement in motor function and was discharged on prednisone. Within one month his condition deteriorated, prompting hospice care.
81-year-old white male with history of stage IV metastatic melanoma with B-Raf positive mutation with metastasis was started on pembrolizumab plus dabrafenib and trametinib. PET-CT scan performed 5 months later reveled extension of metastases prompting a second cycle with pembrolizumab. Patient presented to hospital 5 weeks after with B/L LE quadriparesis. Neurological exam revealed 2/5 UE and 0/5 LE motor strength with areflexia. Lumbar puncture reveled albuminocytologic dissociation (56). He was promptly started on pulse dose solumedrol with IVIG for 5 days. Patient status continued to deteriorate requiring mechanical ventilation due to respiratory failure. Plasmapharesis was initiated but did not show clinical improvement. On day 14, patient had an intracerebral hemorrhage from bleeding brain metastasis prompting hospice consult.
Discussion: PD-1 acts by inhibiting primarily T -cell activation and limits immune effector responses when bound to ligands PD-L1 and PD-L2. Immune checkpoints negatively regulate the immune system to prevent autoimmunity. Monoclonal antibodies targeting PD-1, such as pembrolizumab prevent inhibition of antitumor response, which can lead to autoimmunity. In both cases mentioned above, patients developed AIDP following pembrolizumab. Management included IV steroids and IVIG, with subsequent escalation to plasmapheresis. Given severity of symptoms in these two cases, early recognition of pembrolizumab-induced AIDP is paramount for timely treatment.
| Subject | Nursing | Pages | 7 | Style | APA |
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Answer
PD1 Inhibitors and their Neurological Side Effects
Asia Filatov MD/PhDc, Pamraj Sharma MD, Rupesh Manam MD, Jasmine L. Martin MD, Sean Bhatia MD, Patricio S. Espinosa MD, Sajeel Chowdhary MD
Introduction: Programmed T cell death (PD- 1)
PD-1 are transmembrane proteins on the surfaces of T-cells which act as immune checkpoint regulators and play an important role in the development of auto-immunity and tumor development (Ribas, 2012). With regards to tumors, they prevent the tumor cells from evading immune attack (Shoushtari, Wolchok, & Hellman, 2017). PD-1 inhibitors are monoclonal antibodies that are used in the treatment of certain advanced cancers like small cell lung cancer and multiple myeloma. While they are important in the treatment of such cancers, their actions can lead to exacerbations or development of myasthenia gravis and other auto-immune disorders. A case is hereby presented of a patient who developed myasthenia gravis-like symptoms following treatment with nivolumab.
Case Study One:
An 86-year-old male with a known history of adenocarcinoma of the lung with bony and hepatic metastases presented with a one week history of bilateral ptosis affecting the right eye more than the left, dysphagia and generalized fatigue. He had attained stable disease control with carboplatin and pemetrexed. Maintenance pemetrexed was discontinued after two year after which disease progressed. He had received his first Nivolumab infusion 40 days prior to hospitalization and a third infusion 10 days prior to presentation. Physical examination revealed an alert patient in no distress, had bilateral ptosis which worsened when asked to blink repeatedly but intact extra ocular muscles, had neck discomfort on extension of the C-spine but negative Kernig and Brudzinkis signs, cardiac examination revealed an irregularly irregular pulse with normal s1 and s2, cranial nerves were intact, motor strength was 5/5 bilaterally for both upper and lower limbs, equal reflexes and sensations bilaterally. Laboratory investigations were unchanged from baseline. Lumber puncture and imaging studies were unrevealing. During the period of hospitalization, the patient developed worsening dyspnea, tachypnea and weakness. The patient underwent three sessions of plasmapharesis and five sessions of IVIG daily but showed no clinical improvement. An entire paraneoplastic panel was negative and the confirmation of myasthenia gravis or lambert eaton syndrome was not possible due to negative associated antibodies.
Case Study Two
Pending confirmation of the correct subject
Discussion
The laboratory and imaging studies were inconclusive in this patient. A diagnosis of adverse reaction to the Nivolumab was entertained with the reasoning that the myasthenia like symptoms began after initiation of treatment with Nivolumab. Some of the adverse effects of Nivolumab include pneumonitis, colitits, encephalitis, nephritis and myasthenia gravis (Postow, Sidlow, & Hellmann, 2018).
Mysthenia gravis is an auto-immune neuromuscular disease which causes weakness in skeletal muscles. The commonest muscles involved are extra-ocular, muscles of facial expression, chewing and swallowing. Lambert eaton syndrome is a variant of myasthenia in which immune cells attack calcium channels on nerve endings leading to reduced production of acetylcholine (Kesner, Oh, Dimachkie, & Barohn, 2018). Symptoms in this patient include weakness of ocular muscles and dysphagia. It is often associated with small cell lung cancer especially in the older population.
Nivolumab is a novel anti-tumor drug which has been used in the treatment of non-small cell lung cancer since 2015 (Brahmer et al., 2015). Immune related adverse effects have been documented and include myasthenia gravis (Bramer et al., 2015). A study by Chen, Liu, Hsu, and Chian (2017) presented a case in which a 65 year old man with a history of heavy smoking presented to hospital with progressive ptosis, diplopia and general weakness for one week. He had been diagnosed with a poorly differentiated cancer of the lung and was being treated with nivolumab. They made a diagnosis of Nivolumab induce Mysthenia gravis. Seven cases of myasthenia gravis developing after treatment with nivolumab were also reported by Loochtan, Nickolich, and Hobson‐Webb (2015). In their study, stabilization of myasthenia gravis was achieved but relapsed after nivolumab treatment was started. Of the seven, three patients did not respond to treatment and succumbed. Of note is that all of the affected patients developed mysthenic symptoms within three months of infusion with nivolumab.
References
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Brahmer, J., Reckamp, K. L., Baas, P., Crinò, L., Eberhardt, W. E., Poddubskaya, E., & Waterhouse, D. (2015). Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. New England Journal of Medicine, 373(2), 123-135. Chen, Y. H., Liu, F. C., Hsu, C. H., & Chian, C. F. (2017). Nivolumab-induced myasthenia gravis in a patient with squamous cell lung carcinoma: Case report. Medicine, 96(27), e7350. Kesner, V. G., Oh, S. J., Dimachkie, M. M., & Barohn, R. J. (2018). Lambert-Eaton myasthenic syndrome. Neurologic clinics, 36(2), 379-394. Loochtan, A. I., Nickolich, M. S., & Hobson‐Webb, L. D. (2015). Myasthenia gravis associated with ipilimumab and nivolumab in the treatment of small cell lung cancer. Muscle & nerve, 52(2), 307-308. Postow, M. A., Sidlow, R., & Hellmann, M. D. (2018). Immune-related adverse events associated with immune checkpoint blockade. New England Journal of Medicine, 378(2), 158-168. Ribas, A. (2012). Tumor immunotherapy directed at PD-1. N Engl J Med, 366(26), 2517-2519. Shoushtari, A. N., Wolchok, J., & Hellman, M. (2017). Principles of cancer immunotherapy. Atkins MB, editor.
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