Received Date: March 14, 2016; Accepted Date: April 19, 2016; Published Date: May 19, 2016
Citation: Butt SUR, Bhaumik S (2016) Acute Demyelinating Polyneuropathy Caused by Nivolumab in a Man with Metastatic Non-Small Cell Lung Cancer. J Gerontol Geriatr Res 5:302. doi:10.4172/2167-7182.1000302
Copyright: © 2016 Butt SUR, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Immune checkpoint inhibitors include programmed cell death-1 receptor inhibitors (PD-1), programmed cell death ligand-1 inhibitors and CTLA-4 inhibitors and are novel treatment against certain cancers like non-small cell lung cancer (NSCLC), melanoma and renal cell cancer. They act by boosting the immune response against cancer cells and have improved the prognosis of patients with these cancers significantly shifting the treatment paradigm.
Immune checkpoint inhibitors include programmed cell death-1 (PD-1) receptor inhibitors, programmed cell death ligand-1 (PDL-1) inhibitors and Cytotoxic T-Lymphocyte Associated molecule 4 (CTLA-4) inhibitors and are novel treatment against certain cancers like non-small cell lung cancer (NSCLC), melanoma and renal cell cancer. They act by boosting immune response against cancer cells and have improved prognosis of patients with these cancers significantly shifting the treatment paradigm. Despite their clinical benefit, these agents are associated with the development of immune-related adverse events (IRAEs)  associated with significant morbidity. Immune checkpoint inhibitors such as Ipilimumab and Nivolumab are known to cause immune-mediated acute demyelinating polyneuropathy [2,3]. We hereby report a case of a man with acute demyelinating neuropathy associated with Nivolumab that was treated successfully with high dose intravenous methylprednisolone (IVMP).
A 61-year-old man was diagnosed with a recurrent NSCLC squamous-cell type of left upper lobe of lung 4 months ago and had first-line chemotherapy that he completed 1 month ago. His recent positron emission tomography (PET) scan post-chemotherapy had shown progression of his tumour. He was then commenced on Nivolumab of which he had his first dose 1 week ago. He developed dysaesthesia (numbness and tingling) in his lower limbs 3 days ago that rapidly progressed to bilateral lower limb weakness within 48 hours making him unable to walk and wheel chair-bound by the time he presented to emergency department. This is on the background of 60 pack years of smoking and a primary NSCLC in the right upper lobe of the lung 2 years ago for which he had chemoradiotherapy (Carboplatin and Paclitaxel) with good results at the time. His comorbidities included type-2 Diabetes Mellitus and Gout. He denied having any coryzal symptoms or diarrhoea preceding his weakness. Neurological examination, the patient was afebrile and revealed a preserved consciousness along with a power of 2/5 in proximal and distal muscle groups in both upper and limbs. There was a loss of deep tendon reflexes in all 4 limbs along with a peripheral neuropathy in stocking-pattern. Rest of the neurological exam was unremarkable with no meningeal irritation signs. Laboratory findings including inflammatory markers were unremarkable. A magnetic resonance imaging of whole spine revealed spondyloarthropathy at C4/5 and C5/6 regions and old wedge fractures of vertebral bodies at T7 and T8 with no involvement of spinal cord at any level. Nerve conduction studies showed generalised sensorimotor neuropathic process affecting both lower limbs and upper limbs with features suggestive of a demyelinating process (Tables 1a-1d). These pathological findings are consistent with a diagnosis of the acute inflammatory demyelinating polyneuropathy. A cerebrospinal fluid (CSF) analysis was not performed as according to World Health Organisation-Uppsala Monitoring Centre system for standardised case causality assessment, with a plausible time- relationship to Nivolumab injection and absence of other systemic symptoms, it was almost certain that demyelinating symptoms were secondary to Nivolumab . Upon ceasing Nivolumab and initiating treatment with IVMP 1 gram for 5 days, there was a dramatic improvement in his symptoms and he was discharged home after 5 days. Clinical recovery was nearly complete after 5 days and the patient was completely back to normal by the time of his next clinic appointment in 4 weeks. Prednisolone was tapered off gradually over 2 weeks.
|Site||NR||Peak (ms)||P-T Amp (µV)||Onset (ms)||O-P Amp (µV)||Site 1||Site 2||Delta-0(ms)||Dist(cm)||Vel(m/s)|
|Right Ulnar Dig V Anti-Sensory (Digit V-14 cm)|
|Wrist||3.0||6.0||2.1||4.1||Wrist||Digit V-14 cm||2.1||13.0||62|
|Left Sural Anti-Sensory (Lat Mall)|
|Right Sural Anti-Sensory (Lat Mall)|
Table 1a: Anti-sensory summary table.
|Site||NR||Onset (ms)||O-P Amp (mV)||Site 1||Site 2||Delta-0(ms)||Distance (cm)||Velocity (m/s)|
|Right Peroneal Motor (Ext Dig Brev)|
|B Fib||13.6||0.3||Poplt||B Fib||2.3||9.0||39|
|Left Tibial Motor (Abd Hall Brev)|
|Right Tibial Motor (Abd Hall Brev)|
|Right Ulnar Nerve(Abd Dig Minimi)|
|B Elbow||7.6||7.4||A Elbow||B Elbow||3.3||18.0||55|
Table 1b: Motor summary table.
|NR||F-Lat (ms)||L-R F-Lat (ms)|
|Right Peroneal (EDB)|
|Left Tibial (Abd Hallucis)|
|Right Tibial (Abd Hallucis)|
|Right Ulnar (Abd Dig Min)|
Table 1c: F Wave studies.
|Side||Muscle||Nerve||Root||Ins Act||Fibs||Psw||Amp||Dur||Poly||Recruit||Int Pat|
|Right||Ant Tibialis||Deep Peron||L4-5||Nml||1+||1+||Incr||2+||2+||Rapid||Nml|
Table 1d: EMG.
Anti PD-1 medications are known to cause immune-related adverse events including an immune-mediated Guillain-Barre-like disorder (GBLD) that instead of intravenous immunoglobulins (IVIGs), is managed with high dose corticosteroids . Predisposing factors for the development of the GBLD in patients treated with Nivolumab are not evident while other immunotherapeutic antibodies with a different mode of action have been associated with the same. Antibodies directed against cell-surface gangliosides expressed in human peripheral nerve axon sheath have been linked to the pathophysiology of demyelination although mechanism is not clear, however, immune activation by Nivolumab may cause the demyelination by braking peripheral tolerance to such ganglioside-related epitopes in patients with pre-existing humoral autoimmunity against them .
Checkpoint inhibitors including PD-1 inhibitors in the treatment of NSCLC and other malignancies are being increasingly used and are entering routine oncological practice, and with the number of patients exposed to these drugs increasing dramatically, IRAEs are becoming more common as well. Clinicians and junior doctors should be aware of these possible rare adverse effects and their management. AIDP is rare but potentially debilitating and possibly life-threatening adverse event and while high-dose IVIGs or plasmapheresis is the recommended therapeutic option for classic Guillain-Barre syndrome (GBS), a treatment with high dose IVMP is the mainstay of the treatment for immune-mediated acute GBLD, which is considered to be non-active in the classical presentation of GBS.
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