Oxaliplatin-Induced Acute Peripheral Nerve Hyperexcitability

Authors: Hee-Jae Jung, Kwanju Song, Young-Min Lim, Hyunjin Kim

Dear Editor,

Oxaliplatin is a platinum-based chemotherapeutic agent that is widely used for solid tumors, particularly colorectal cancer.1 Although effective, oxaliplatin is associated with neurotoxicity that significantly impacts the quality of life of patients.2 This neurotoxicity manifests as either chronic sensory axonal neuropathy or neuronopathy, or as acute reversible symptoms of peripheral nerve hyperexcitability.2 We report a case of acute neurotoxic symptoms following initial oxaliplatin treatment, which resolved completely within 3 weeks after discontinuation.

A 53-year-old female developed dysarthria, bilateral lower extremity weakness, paresthesia, and widespread muscle twitching immediately after receiving her first treatment with intravenous oxaliplatin (200 mg over 2 hours). She had undergone surgery 1 month previously for dual primary colon adenocarcinoma and clear-cell renal cell carcinoma. A neurologic examination revealed paraplegia (Medical Research Council [MRC] grade I), widespread fasciculations, and delayed relaxation of hand grip (Supplementary Video 1 in the online-only Data Supplement). Pinprick sensations were slightly decreased in the distal parts of the upper and lower limbs, and vibration sensations were slightly impaired in both big toes. Hyperactive deep tendon reflexes were present in all limbs, without Hoffmann’s or Babinski signs. Other examination findings were unremarkable, including the mental status and cranial nerves. Notably, the paraplegia improved to MRC grade IV within 9 hours.

Laboratory tests were unremarkable, including electrolyte total calcium (9.3 mg/dL, normal range 8.6–10.2 mg/dL), ionized calcium (4.76 mg/dL, normal range 3.9–4.5 mg/dL), sodium (141 mmol/L, normal range 135–145 mmol/L), and potassium (4.1 mmol/L, normal range 3.5–5.1 mmol/L). Nerve conduction studies of the bilateral median, ulnar, tibial, and peroneal nerves revealed repetitive compound muscle action potentials (Fig. 1A and B). Needle electromyography identified neuromyotonic and myokymic discharges in the abductor pollicis brevis, first dorsal interosseous, and tibialis anterior muscles (Fig. 1C, D, and Supplementary Video 1 [in the online-only Data Supplement]). Magnetic resonance imaging of the brain and spinal cord showed no abnormalities. Additionally, serum assays for anti-LGI1 (leucine-rich glioma inactivated-1) and anti-CASPR2 (contactin-associated protein-like 2) antibodies were negative. Conservative management with daily duloxetine (30 mg), pregabalin (150 mg), and clonazepam (0.5 mg) was implemented for 1 month, leading to gradual symptom resolution over 3 weeks (Supplementary Video 1 in the online-only Data Supplement). The patient remained stable even after discontinuing these medications. Subsequent oxaliplatin treatments were administered at a slower infusion rate, reduced from the previous rate of 100 mg/h to 50 mg/h. This adjustment did not lead to symptom recurrence.

Oxaliplatin-induced neurotoxicity presents in two 1) chronic, cumulative sensory axonal neuropathy or neuronopathy, and 2) acute symptoms of peripheral nerve hyperexcitability.2 Acute peripheral nerve hyperexcitability is commonly associated with disruptions in voltage-gated potassium channels (VGKCs), as seen in neuromyotonia.34 VGKCs play a critical role in repolarizing neuronal membranes after the generation of action potentials. Dysfunction in VGKCs leads to prolonged depolarization phases, causing excessive neurotransmitter release, repetitive neuronal firing, and augmented muscle contraction. This induces characteristic symptoms such as fasciculations and myokymia.1

In contrast, the acute nerve hyperexcitability following oxaliplatin treatment may involve temporary dysfunction of sodium channels.12567 The oxalate derivative of oxaliplatin chelates calcium ions, indirectly influencing the kinetics of voltage-gated sodium channels by altering the axonal membrane potential.18 This modification may increase the refractoriness of motor axons, resulting in acute functional channelopathy of sodium channels.9 Experimental studies have shown that oxaliplatin exposure modulates the inactivation kinetics of sodium channels, shifts both their activation and inactivation thresholds, and reduces the overall sodium current.910 These transient, dose-dependent, and reversible changes can promote ectopic neuronal activity, leading to multiple neuromyotonic-type repetitive discharges in motor axons, which are correlated with the clinical presentation of acute paresthesia and fasciculations.9

The initial paraplegia observed in the present case is unusual for oxaliplatin-induced hyperexcitability, since most reported cases present with less weakness. The rapid improvement to MRC grade IV within several hours suggests a transient, reversible channelopathy rather than structural nerve damage. This highlights possible individual susceptibility to oxaliplatin-induced ion-channel dysfunction, warranting further investigations into patient-specific risk factors.

The management of acute neurotoxicity relies on stabilizing ion-channel function. Duloxetine, pregabalin, and clonazepam were effective at mitigating the symptoms in the present case, while modifying the oxaliplatin infusion rate prevented recurrence. These findings underscore the importance of personalized treatment strategies when managing oxaliplatin-related neurotoxicity.

Accurate diagnosis is critical for distinguishing oxaliplatin-induced acute peripheral nerve hyperexcitability from other neurologic conditions. Nerve conduction studies and needle electromyography are essential for identifying characteristic repetitive compound muscle action potentials, as well as neuromyotonic and myokymic discharges. These diagnostic tools enable timely and targeted interventions that will reduce the neurotoxic burden and improve patient outcomes.

This case highlights the importance of recognizing and managing oxaliplatin-induced acute neurotoxicity. Understanding the underlying mechanisms and employing tailored treatment strategies can prevent recurrence and improve the quality of life of patients receiving chemotherapy.