Autonomic neuropathy resulting in recurrent laryngeal nerve palsy in an HIV patient with Hodgkin lymphoma receiving vinblastine and antiretroviral therapy

Introduction

Hoarseness of voice due to vocal cord paralysis as a result of recurrent laryngeal nerve (RLN) palsy is widely recognised. ¹ There are several causes of RLN palsy. Lung neoplasm and pulmonary tuberculosis are the most common. ¹ Vinca alkaloids are neurotoxic and usually cause peripheral neuropathy. ² However, cranial mononeuropathies are rarely recognised as side effects of vinca alkaloids. ³ We report an HIV-positive man who developed unilateral vocal cord palsy during treatment of Hodgkin lymphoma (HL).

Case report

A 48-year-old HIV-positive man presented with hoarseness of voice. HIV infection had been diagnosed four years previously. The patient started receiving antiretroviral therapy in the form of tenofovir, emtricitabine and nevirapine. He remained well for that time.

In May 2012, he presented with weight loss and left sided chest pain. His CD4 count was 388 cells/mm³ and HIV RNA level was undetectable. Chest computed tomography (CT) scan showed mediastinal and bilateral hilar lymphadenopathy measuring 4 cm in diameter on the left side, as well as retroperitoneal lymph node enlargement on abdominal CT scan.

Computerised tomography scan-guided core biopsy was taken from retroperitoneal lymph nodes. The latter was suggestive of HL lymphocyte depleted type, stage IVB extranodal extension and splenic involvement (ES).

This patient received doxorubicin 25 mg/m², bleomycin 10 units/m², vinblastine 6 mg/m², dacarbazine 375 mg/m² (ABVD) in line with British HIV Association guidelines for HIV-associated malignancies. ⁴ He continued to take combination antiretroviral therapy (cART) during and after chemotherapy. Two weeks after commencing chemotherapy, he complained of hoarseness of voice without any symptoms of peripheral neuropathy or infection. Clinical examination revealed no neck swelling, masses, lymphadenopathy or peripheral neuropathy. He remained symptomatic following completion of three cycles of ABVD out of a total six. Whole body positron emission tomography (PET) scan showed excellent response to treatment with no evidence of residual tumour.

When the hoarseness of voice had worsened during fourth cycle of chemotherapy, a flexible nasoendoscopy was performed which reported paralysis of the left vocal cord in an abduction position. Consequently, vinblastine was omitted from the last two cycles. Three weeks later, his symptoms completely resolved. A repeat flexible nasoendoscopy showed that his left vocal cord returned to normal position.

Discussion

Vinca alkaloid-related vocal cord paralysis has been reported infrequently in the literature.^3,5–8 The degree of toxicity is related to the dose, and if other drugs such as allopurinol, erythromycin, isoniazid, phenytoin and itraconazole are concomitantly used.^9–11

Our patient was receiving tenofovir, emtricitabine and nevirapine at the time of development of vocal cord palsy. Vinblastine is metabolised by CYP3A4. Nevirapine can induce or inhibit the metabolism of vinca alkaloids. However, there is evidence that CYP3A4 is involved in the detoxification of vinblastine. Thus, inhibition of the metabolism of vinca alkaloids would be expected to increase the risk of common dose-related toxicities.^12–13 Emtricitabine and tenofovir co-administration with vinblastine has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. ¹⁴

The use of concomitant cART and chemotherapy remains controversial in the management of AIDS-related haematologic malignancies. In a retrospective study, 32 HIV-infected patients with HL treated with chemotherapy appeared to experience more neurotoxicity compared to HIV-negative patients. Moreover, the use of ritonavir in HIV-positive patients in combination with vinblastine was associated with an increased risk of neurotoxicity.^15,16 While there are concerns about increased toxicity and potential interactions, the use of cART in the treatment of HL has the potential to improve cancer outcomes. ¹⁶

Involvement of vocal cords has been described in the literature as unilateral or bilateral. The left vocal cord is predominantly involved probably due to its long course in the thorax and paralysis commonly occurs during early phases of chemotherapy implying that even smaller doses of a relatively less neurotoxic vinca alkaloid are capable of causing nerve damage. ¹⁷ Recurrent laryngeal neuropathy should be suspected in all patients presenting with a new onset of hoarseness, dysphagia or stridor being treated with vinca alkaloids. Hence, early involvement of an ENT surgeon is important to rule out other causes such as laryngeal cancer.

In this case, there was no evidence of residual viable tumour on PET scan and with the absence of identifiable pathology to explain the RLN palsy, it was believed that the presumptive diagnosis of vinblastine-related RLN paralysis was confirmed. We believe vinblastine led to the development of vocal cord paralysis due to temporal association with the drug and lack of alternate explanation.

Like other similar cases, we found that vocal cord paralysis completely recovered after the drug was withdrawn. Most of the authors reported that complete recovery of paralysis required one week to four months.^3,5,6,18 Our patient was given full dose of vinblastine in four cycles. However, due to excellent response to treatment, vinblastine was omitted from the last two chemotherapy cycles rather than dosage adjustments being made. His symptoms resolved within three weeks.

In conclusion, our patient developed RLN palsy whilst on vinblastine. Chest CT scan ruled out compression of the RLN. Although the neurotoxicity of vinca alkaloids is widely known, cranial nerve neuropathy is rare. The co-administration of antiretroviral therapy may have exacerbated this. HIV physicians need to be aware of this potentially reversible side effect in order to prevent potential life-threatening stridor and should not assume that the patient’s lymphoma is advancing.