Vincristine-Induced Seizure from Drug Interactions: A Case Report and Review of Literature.

Introduction

Vincristine (VCR), as one of the most extensively used cytotoxic agents, has a labeled indication for the treatment of acute lymphoblastic leukemia (ALL) [1] . The significant adverse effect of VCR and Vinca alkaloids is neurotoxicity, which appears to be dose dependent and cumulative. Patients receiving VCR may develop peripheral neuropathy, sensory deficits, muscle weakness, altered mental status, and seizures during the treatment [2] . Neurotoxicity usually occurs within 4–10 days of VCR administration, with most symptoms disappearing by about the sixth week after discontinuation of therapy [3] . Coadministration of VCR with other neurotoxic agents, a history of spinal cord irradiation, and drug interactions that cause increased serum concentrations of VCR are known to raise the risk of VCR-induced neurotoxicity. On the other hand, seizures are common in patients suffering from ALL and can be caused by intracranial metastasis, anticancer drugs, and metabolic disorders (e.g., hyponatremia) [4] .

Here, we present a case of an adult patient with ALL who developed seizures, possibly from VCR and its drug interactions. Further, we review the literature regarding the mechanisms, risk factors, and strategies for the prevention and management of vincristine-induced seizure (VIS). The main reason for reporting this case study is that to the best of our knowledge, most of the cases with neurological complications of VCR have been reported in children, and there is little information about this adverse effect in the population of adult patients. Further, reports of enhanced VCR neurotoxicity from drug interactions are limited too.

Case Presentation

A 29-year-old man with an 83 kg weight and a height of 173 cm presented with weakness, lethargy, and fatigue to the emergency department of a tertiary university-affiliated hospital in Iran in December 2021. His physical examination revealed purpura and petechiae, and a complete blood count (CBC) showed severe anemia (hemoglobin = 6.4 g/dL), thrombocytopenia (platelets = 93,000/μL), and leukocytosis (white blood cells = 23,100/μL). The bone marrow aspiration and biopsy examination confirmed pre-B-cell ALL with more than 90% blasts. The patient had a history of seizures from childhood that were controlled with oral sodium valproate (500 mg twice daily). He was referred to the hematology ward to initiate chemotherapy with the Cancer and Leukemia Group B (CALGB) 8811 regimen, course I, induction (cyclophosphamide 1,200 mg/m 2 intravenously [i.v.] on day 1, VCR 2 mg/m 2 i.v. on days 1, 8, 15, 22, doxorubicin 30 mg/m 2 i.v. on days 1–3, and oral prednisolone 60 mg/m 2 daily on days 1–21). The patient also received oral itraconazole (200 mg twice daily), acyclovir (400 mg twice daily), and ciprofloxacin (500 mg twice daily) to prevent neutropenia-related infections which were initiated on the first day of the chemotherapy, plus sulfamethoxazole/trimethoprim (400/80 mg daily) for pneumocystis pneumonia prophylaxis. Further, tumor lysis syndrome prophylaxis was achieved with i.v. hydration (3 L of isotonic saline) and oral allopurinol (100 mg 3 times a day).

On day 3, shortly after the end of doxorubicin infusion, the patient developed an episode of a generalized tonic-clonic seizure lasting 2–3 min, followed by a 30-min postictal loss of consciousness. Immediately after this event, his blood pressure was 115/67 mm Hg, heart rate 85 beats/min, and oxygen saturation 98%. Laboratory data revealed normal serum electrolytes, blood urea nitrogen, and blood glucose. The level of sodium valproate was reported to be 117 μg/mL (therapeutic range: 50–150 μg/mL). Inflammatory markers such as the erythrocyte sedimentation rate and C-reactive protein were also in the normal range, and he was afebrile with no discernible infectious state. A lumbar puncture was performed, and cerebrospinal fluid analysis revealed 20 mg/100 mL total protein, 6% Gamma globulin, 60 mg/100 mL glucose, two white blood cells (all mononuclear), and no red blood cells. The electroencephalogram was normal. Computed tomography scans and magnetic resonance imaging (MRI) of the brain indicated no abnormalities or evidence of hemorrhage or midline shift ( Fig. 1 ). Thus, central nervous system (CNS) involvement due to ALL and CNS infection and inflammation was ruled out. Finally, according to the Naranjo Adverse Drug Reaction (ADR) Probability Scale [5] , his seizure was classified as being probable (score +5) related to the VCR. Thus, with this possibility and concern of recurrence of seizures, despite the existence of sufficient evidence that VCR is culpable, VCR was discontinued. The patient received a continuation of the CALGB regimen without VCR and remained in complete remission on conventional maintenance therapy with no evidence of neurological sequelae. The patient did not have any other episodes of seizure until his discharge.

Literature Review and Discussion

We reported a case of adult ALL with a history of controlled childhood seizures who developed seizures on the treatment of CALGB 8811 protocol, possibly secondary to VCR enhancement following coadministration with itraconazole and doxorubicin. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000530655 ).

Based on a search in “Google Scholar” and “PubMed,” English literature with keywords “Vincristine,” “Vinca Alkaloid,” “Neurotoxicity,” “Seizure,” “Epilepsy,” “Chemotherapy-Induced Neurotoxicity,” “Vincristine-drug Interactions,” “Drug-drug Interaction,” “Antifungal drugs,” “Itraconazole,” and “Doxorubicin,” with relevant content has been collected. Available reports of VIS in adult patients are summarized in Table 1 .

Introduction of VCR

VCR is a Vinca alkaloid used primarily as a combination of chemotherapy drugs in leukemia, lymphoma, neuroblastoma, and sarcomas. VCR is a critical drug in the hyper-CVAD and CALGB regimens that have been successfully used in adult ALL [1, 10] . The mechanism of action of VCR has been related to the inhibition of microtubule formation in the mitotic spindle, resulting in an arrest of cell division at the metaphase stage and inhibition of nucleic acid synthesis due to decreased RNA polymerase, dihydrofolate reductase, and thymidylate synthetase [1, 10] . The metabolism of VCR is extensively hepatic via cytochrome P450 3A4 (CYP3A4) and is also a minor substrate of P-glycoprotein/ABCB1 [10, 11] . Thus, CYP3A4 inducers and inhibitors may elevate or reduce the serum concentrations of VCR, respectively.

Neurotoxicity of VCR

Among the Vinca alkaloids, VCR is the most neurotoxic. The CNS involvement due to VCR is less common than peripheral and autonomic neuropathy and may include seizures, encephalopathy, ataxia, athetosis, coma, transient cortical blindness, parkinsonism, and cranial nerve mono-neuropathies (oculomotor) [2–4, 12] . VIS is a dose-limiting side effect, with the incidence varying from 4.5% to 15.1%. In these reports, the latency between the last dose of the drug and the occurrence of seizures ranged from a few hours to several days [13] . However, seizure is the most common presenting symptom of posterior reversible encephalopathy (PRES). PRES is rare and characterized by cerebral edema with bilateral and symmetric involvement of the white matter of the occipital and parietal regions. MRI most easily demonstrates this involvement [14] . Data support the association between VCR and PRES incidence [15–17] . Obviously, there is a case report in 1988 about the occurrence of PRES caused by VCR in the induction phase in 8-year-old children with ALL [15] .

Mechanism of VIS

Although reports of VIS are old and, to the best of our knowledge, the first reports dated back in 1966 [18] , the mechanism of this ADR is not entirely clear. The occurrence of hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion has been suggested as a possible cause for VIS. It has been hypothesized that VCR acts on the hypothalamic nuclei to stimulate antidiuretic hormone (ADH) release. It is also possible that VCR itself has an ADH-like activity [19, 20] . In addition, VCR has a direct neurotoxic effect on the CNS. This hypothesis is based on finding neuronal lesions in the cerebellum, pons, medulla and autopsy in patients with ALL who were treated with VCR. These changes are commensurate with those induced in animals by VCR [12, 20] .

Risk Factor for VIS

Risk factors for VIS are both patient related and drug related. A history of seizure, leukoencephalopathy, cerebral infarction, cerebral hemorrhage associated with thrombocytopenia, hypertension, liver disease, and metabolic disturbances has been reported as patient-related risk factors for developing VIS in patients on VCR therapy [12, 18–21] . The neurotoxic potential of VCR might increase following continuous infusion of the drug [7] . Although there is a significant relationship between the dose plus duration of VCR therapy and the risk of VIS [22–25] , there is also a case report of a VIS in a patient receiving a therapeutic dose of VCR and no significant identifiable contributing factors [26] . VCR interaction with the substrates and inhibitors of CYP3A4, such as the azole antifungals, isoniazid, cyclosporine, and nifedipine, which interfere with VCR metabolism, is another crucial risk factor for VIS [11, 27, 28] .

VCR-Azole Interactions

To varying degrees, all azole antifungal agents are affected and metabolized by the hepatic CYP450 enzymes ( Table 2 ) [11, 29, 30] . Concomitant use of VCR and azoles resulting in elevated VCR serum concentration is associated with an increased risk of neurotoxic effects of VCR such as seizures [12] . According to the period for the elimination of VCR, interaction time should have been approximately 5–7 days after coadministration with azole agents [28, 31] . VIS has been reported to be developed within 15 days on average (range 9–28 days), which may occur because the enzyme inhibition lasts for a more extended period, resulting in delayed neurotoxicity symptoms such as seizures [13, 30] . In a retrospective study conducted by Lihua Yang et al. on 68 child patients with ALL who received VCR and triazole agents, the seizure rate was significantly higher in the itraconazole and voriconazole groups than in the fluconazole and control groups [13] . Also, in subgroup analysis, the seizure risk was significantly higher in the itraconazole group than in the voriconazole group. The seizure rate in this study was reported in nearly 9% of cases. In another comprehensive analysis of adverse drug interactions of VCR, the seizure rate was reported at 23.4%, which occurred only in the children whose VCR was administered concomitantly with azole antifungals, with the highest rate for itraconazole [11] . A study by Andrew B. Smitherman et al. on 197 child patients with ALL, 160 of whom received fluconazole as antifungal prophylaxis, revealed that coadministration of fluconazole during induction therapy for pediatrics with ALL did not significantly increase the risk for VCR toxicities; however, 10-year-old patients and older were at an increased risk for VCR toxicity independent of fluconazole exposure [32] .

Although the concomitant use of VCR and azoles has increased, there are currently no evidence-based guidelines concerning this potential neurotoxic interaction, and clinical decisions are based mainly on expert opinion. For patients receiving itraconazole, posaconazole, or voriconazole, it may be reasonable to withhold these agents before VCR chemotherapy. However, this may be logistically difficult with azoles with a long half-life, such as itraconazole and posaconazole. So, enzyme inhibition is prolonged and can continue even after azole agent discontinuation [11] . Withholding voriconazole before VCR may also be complicated in patients who are CYP2C19 poor metabolizers, as the half-life of voriconazole is extended in these patients [11] . Alternatively, a substitute azole antifungal agent with minimal interference, such as fluconazole, or another class without or with minimal interaction, such as echinocandin and amphotericin B, may be administered. Dose reduction of VCR should be considered in individuals with a probable or possible invasive fungal infection where azole therapy is required and alternative antifungal therapies are contraindicated or inappropriate [11, 33] . Regardless, this approach is not recommended in the absence of VCR drug level monitoring [11] .

VCR-Doxorubicin Interactions

There are some cases of seizures due to concomitant use of VCR and doxorubicin [6, 20] . Regarding the possible mechanism, doxorubicin may be involved in neurotoxicity with the possible synergism with VCR [6] .

Management of Patients with VIS

No specific treatment has been proposed for the management of VIS. Different antiepileptics have been applied in the case reports and case series based on the type of seizures. Moreover, there is no consensus on whether VCR should be discontinued or not after developing VIS. Of note, due to permanent and irreversible sequelae followed by recurrent convulsions, withholding VCR in patients who develop convulsions seems reasonable [20] .

Note that managing the underlying causes of VIS and developing prevention strategies is most important. Symptomatic treatment of syndrome of inappropriate antidiuretic hormone secretion associated with VCR is mainly based on fluid restriction with the administration of hypertonic saline solution and i.v. furosemide [17, 34] . Correspondingly, it is necessary to be wary of conditions known to aggravate VCR’s neurotoxicity, such as concurrent use of other drugs with neurotoxic possibilities, drug interaction, and electrolyte abnormalities (e.g., hyponatremia) [34] .

Our Patient, the Challenges, Outcome, and Limitations

According to the Naranjo ADR Probability Scale, a probable relationship between seizure and VCR therapy was indicated in our patient. The Naranjo Scale has been developed to estimate the probability of an ADR, with scores ranging from 0 to 13, with a higher score suggesting a more substantial probability [5] . Using this scale, we calculated a score of 5, which offers a probable reaction. However, the basis of the Naranjo Scale is expert opinion and consensus. But it is currently one of the few tools available to assess the probability of ADRs. Although our patient had a history of childhood seizures, the seizures were controlled, with the rejection of other underlying causes and lack of evidence of electrolyte disturbance or an abnormality in the brain and cerebrospinal fluid; it appears that the patient currently has seizures due to ADR. It should be noted that due to the normality of the MRI and the absence of other associated symptoms, such as headache, visual disturbance, acute hypertension, and other central nervous signs and symptoms, PRES was not considered for our patient. It seems that in our patient, due to the risk factor for seizure, choosing an antifungal from another category with minimal interaction, such as echinocandin or amphotericin B, was the most appropriate course of action. Also, we could not measure urine sodium, urine and serum osmolarity, ADH level, and arterial blood gas. Also, therapeutic drug monitoring of VCR and itraconazole was not performed for this patient. Our patient did not have any other episodes of seizure until his discharge and at a 3-month follow-up.

Conclusion

We presented a case of an adult pre-B-cell ALL patient with a history of controlled childhood seizures who developed seizures after the CALGB 8811 regimen, possibly secondary to concomitant use of VCR with itraconazole and doxorubicin. Patients with clinically significant risk factors such as a history of seizures and VCR-drug interactions appear to have a greater risk of developing seizures and should be monitored closely during chemotherapy. Clinicians should be aware of the possibility of VIS in adult patients, especially with the concomitant use of drugs known to have potential drug-drug interactions. It is recommended to use preventive strategies such as using drugs with minimal interaction. In addition, it is recommended to maintain the patient’s electrolyte levels in the normal range. Measuring the blood level of VCR and reducing its dose if needed can also be among other appropriate considerations.

Acknowledgments

The authors wish to acknowledge all treatment staff involved in patient management.

Statement of Ethics

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. This study protocol was reviewed and the need for approval was waived by the Research Institute for Oncology, Hematology, and Cell Therapy affiliated to Tehran University of Medical Sciences.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Author Contributions

S.H., M.P., and B.S.: literature review, selecting articles, and writing the original format of the article, D.B., S.A., Sh.A., M.V., and M.H.: edited, reviewed, and provided guidance and helpful feedback on the draft. All authors contributed to patient management and prepared the final version of the manuscript.

Funding Statement

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Data Availability Statement

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.

Supplementary Material

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Associated Data

Supplementary Materials

Data Availability Statement

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.