Severe Generalized Weakness,Paraplegia following administration of Oxaliplatin in a patient with refractory T-cell non-Hodgkin lymphoma: A case report

Introduction

Oxaliplatin is a third-generation platinum compound that used extensively for the treatment of various types of cancer, including gastrointestinal and gynecologic cancer. ¹ Side effects of platins include nausea, vomiting, diarrhea, mucositis, stomatitis, pain, alopecia, anorexia, cachexia, anaphylaxis, cytopenia, hepatotoxicity, ototoxicity, and cardiotoxicity. ² However, the main dose-limiting toxicities of oxaliplatin are hematological toxicity and peripheral sensory neuropathy. ³ Peripheral neurotoxicity is one of the most substantial limitations of oxaliplatin administration in cancer treatment. ⁴ Acute and chronic oxaliplatin-induced neuropathy can be distinguished by time, duration, and clinical symptoms. ⁵ Acute oxaliplatin neurotoxicity is triggered or aggravated by exposure to cold and is clinically characterized by distal sensory impairment consist of dysesthesia and paresthesia that occur during or within few hours following oxaliplatin administration. ⁶ It is characterized with rapid onset, and transient features. Moreover, it occurs often in all patients.^7,8 The chronic form is cumulative dose-dependent and due to the repeated administration of chemotherapy (CT) courses. It may continue for several months which leading to detrimental effects on quality of life. ⁴ These effects are thought to be mediated by interaction of oxaliplatin with voltage-gated sodium channels in peripheral nerves. ⁶ At present, there is not an efficacious preventive strategy for oxaliplatin-induced peripheral neuropathy and pharmacologic options for the treatment is limited. ⁶

Gemcitabine, a pyrimidine nucleoside analog, is considered as a new promising agent in the treatment of cancer. ⁹ The drug has exhibited activity against a variety of solid tumors and lymphoma.^10,11 The most reported adverse effects include myelosuppression, elevated liver enzymes, and influenza-like syndrome. Neurotoxicity and renal dysfunction with gemcitabine is rare. ¹² Neuropathy has been seen in less than 6% of people treated and presenting as paresthesia. ¹³

Here we report a case with a rare complication of combination therapy with oxaliplatin and gemcitabine, i.e. severe generalized weakness, Paresthesia and Paraplegia. In order to write this manuscript, we obtained informed consent from the patient.

Case presentation

A 42-year-old Iranian man without any past medical history who first presented with stage 4 non-Hodgkin's lymphoma. The sites of involvement were bilateral neck lymphadenopathy, mediastinal lymphadenopathy, and extensive involvement of the parenchyma of both lungs. At the onset of the disease and until hospitalization due to paraplegia, the patient had no symptoms of neurological involvement. The diagnosis of peripheral T-Cell lymphoma (PTCL) was confirmed by biopsy of the cervical lymph nodes and pathological and immunohistochemical examinations. The patient received 5 cyclophosphamide, hydroxydaunorubicin, oncovin, prednisolon (CHOP) cycles in the first line of treatment. The sixth cycle of treatment was not prescribed due to the patient's delay response and disease progression. It should be noted that the interim evaluation of the patient by contrast enhanced computerized tomography (CT) scan showed a near-complete response. The patient had an Eastern Cooperative Oncology Group performance status of 1 to receive high-dose chemotherapy and autologous transplantation, so, the ICE (ifosfamide, carboplatin, etoposide) salvage chemotherapy regimen began. Unfortunately, after receiving three cycles of this chemotherapy regimen, his systemic symptoms, including fever and drenching sweet, persisted. Although the involved nodal areas had a significant regression in the CT scan evaluation, but fluorodeoxyglucose-positron emission tomography CT scan showed no response to treatment. Then the patient started the third line of treatment with GEMOX chemotherapy. In January 2021, he received her third cycle of salvage chemotherapy using gemcitabine, oxaliplatin (GEMOX) (oxaliplatin 100 mg/m², IV infusion in 500 ml dextrose 5% over 2 h, gemcitabine 1000 mg/m², IV infusion in 500 ml normal saline with the rate of 10 mg/m²/min). Prior to beginning therapy with GEMOX, his electrolyte levels were checked, which were in the normal range. Three days after receiving his GEMOX regimen, he was brought to the hospital emergency department with complaint of severe generalized weakness, paresthesia in the upper extremities, and paraplegia in the lower extremities in a wheelchair-bound status. Physical examination of our patient indicated the absence of bilateral lower extremity reflexes, lower extremity weakness (one out of five), upper extremity weakness (three out of five), saddle anesthesia and weak rectal sphincter tone. Sensation to pain was absent in his lower extremities from the inguinal region. Other findings on physical examination were unremarkable. The patient was admitted to the hospital with suspected spinal cord compression. Nonetheless, magnetic resonance imaging with gadolinium of his whole spine (neck, thoracic, lumbar and sacral regions) did not show any evidence of cord compression (Figure 1).

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Figure 1.

Magnetic resonance imaging (MRI) with gadolinium of patient's whole spine (neck, thoracic, lumbar and sacral regions).

Lumbar puncture was performed to rule out cerebrospinal metastases. Cerebrospinal fluid cytology and flow cytometry were negative for malignancy. Furthermore, electromyography (EMG) was performed for patient that reported chronic sensorimotor polyneuropathy with ongoing axonal loss (Figure 2). Based on Naranjo score (Score = 6), this adverse effect was probably due to oxaliplatin. ¹⁴ The full scoring grid has been sent in a separate supplemental file.

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Figure 2.

Electromyography (EMG) results of patient.

Intravenous dexamethasone 8 mg three times daily was started at the time of admission for the patient. Muscle weakness and sensory impairment improved dramatically within 10 days and the patient was able to walk with assistance. On examination, the muscle strength in the lower limb increased to four out of five and he fully recovered in the upper limb. The patient was discharged with an appointment at the outpatient clinic. Due to the patient's general health conditions and the stable disease, no new chemotherapy for his refractory lymphoma was prescribed.

Several cases of neuropathy following oxaliplatin and only one case with gemcitabine-based chemotherapy regimen have been previously reported. Most of these cases involved the development of dysarthria, Paresthesia, with associated ataxia.

Oxaliplatin is a platinum-based cytotoxic agent that its cytotoxic effect is possibly as a result of interference with DNA replication through the formation of DNA adducts. ¹⁵ The typical neurotoxicity of oxaliplatin has been associated with the accumulation of di-chloro-DACH platinum, a biotransformation product of DACH (diaminocyclohexane) platinum's in the axonal and dorsal root ganglia neurons. ¹⁶ The cumulative neurotoxicity is linked to a concurrent enhancement of intra-erythrocytic oxaliplatin concentrations.^16,17

To date, motor symptoms mostly occurred only in the setting of acute neuropathy, although the cumulative dose-dependent chronic neuropathy induced by oxaliplatin has been characterized as a sensory neuronopathy with sparing of motor fibers. It has been seen in 10–15% of patients after cumulative doses of 780–850 mg/m². ⁶ The most striking finding of our study was the incidence of a chronic sensorimotor axonal-demyelinating polyneuropathy in a patient who were subjected to oxaliplatin therapy. Mechanistically, Wilson et al. exhibited notable sign of peripheral motor nerve hyperexcitability in serial EMG examination following oxaliplatin administration. Nevertheless, there was no report of paraplegia. ¹⁸ It seems repetitive compound muscle action potentials could lead to paraplegia in chronic exposure. In another study, six patients after 8–9 course of chemotherapy showed a considerable reduction in the sensory nerve action potential of upper limb (median, radial, and ulnar nerves) and right lower limb (sural nerve), without an alteration in conduction velocity, pointing to the loss of sensory neurons or sensory fibers. ¹⁹ The exact mechanism of oxaliplatin-induced neurotoxicity is not clear. However, it is proposed that oxaliplatin leads to a persistent opening of sodium channels and distruption of ion channels in some sensory nerves and cause a hyperexcitable status.^19,20 Grolleau et al. reported that oxaliplatin effects sodium currents through chelation of calcium by oxalate (a metabolite of oxaliplatin). ²¹ Rodent studies have exhibited platinum accumulation in dorsal root ganglia leading to changes in cell morphology. ²² Several neuroprotective strategies for oxaliplatin-induced neurotoxicity have shown limited success. Approaches to regulation of Na channels at axonal have been performed with mixed findings, proposing that various procedures may be required to specially target oxaliplatin-induced modulation of Na channel function. ²³

Conclusions

We report a case of severe generalized weakness and paraplegia following administration of Oxaliplatin. Our case supported that oxaliplatin treatment can be associated with a detrimental disabling neuropathy that may have a portion of motor. Further researches are needed to precisely ascertain the effect of oxaliplatin on motor nerves in both acute and delayed neuropathy.