DISCUSSION:
Exposure to chemotherapy may conceivably represent an environmental trigger for LHON conversion, as the pathophysiology of LHON is postulated to involve cellular apoptotic sensitivity. Neurotoxicity is a well-known possible complication of chemotherapy such as platinum agents, taxanes and bortezimib, typically occurring in a dose dependent fashion with pre-existing neuropathies serving as important potential risk factors. In this way, patients with congenital neuropathies presenting with malignancy pose a difficult challenge in selecting the appropriate chemotherapy regimen to both minimise toxicity and provide optimal efficacy.
In consideration of the cytotoxics used in our case, although cisplatin commonly causes large fibre sensory neuropathy it could also have been thought to mediate mitochondrial damage relevant to the pathogenesis of LHON. Cisplatin preferentially has uptake in the dorsal root ganglia resulting in a dose dependent large fibre sensory neuropathy. The mechanism thought to underpin this involves DNA binding and interruption of synthesis which has been shown to cause inhibition of axonal growth, alterations to sensory ganglion cell body nucleoli and neuronal atrophy. These effects however may manifest at lower cumulative dose totals if risk factors including a background history of neuropathy are present. Cisplatin has also been shown to mediate mitochondrial damage in tumour bearing mice studies via the oxidation of proteins and lipids via decreased antioxidant activity and increased free radicals. Furthermore, data linkage studies have demonstrated an association between cisplatin-induced ototoxicity and mitochondrial haplogroup J (also associated with LHON). Cisplatin neuropathy could theoretically also be mediated via alternate mitochondrial pathways, affecting those with mitochondrial mutations who may be more vulnerable. It is interesting that despite these theoretical risks of exposure and the potential role for the mitochondrion in the pathogenesis of certain chemotherapy toxicity, this was not supported in our case. One explanation for this could be through viewing LHON as a disorder predominantly of ’mitochondrial dysfunction’ as opposed to being mediated via the same cytotoxic biomolecular pathways in which chemotherapy classically exert their neuropathic effects. Other drugs which are known to cause conversion of LHON are associated with mitochondrial effects, including erythromycin which was shown to cause blindness in one LHON patient as well as inhibition of cybrids containing their 11778 mitochondrial DNA. On this basis, chemotherapeutic choice may then be analysed based on their risk to the mitochondrion and ROS generation rather than purely neuropathy risk. There are two other documented cases in the literature of successful administration of chemotherapy in LHON patients. The first case report detailed the successful treatment of a 36-year-old male with LHON (11778 mtDNA mutation) and stage IIA non-Hodgkin’s lymphoma with six cycles of dose reduced cyclophosphamide, vincristine, epirubicin and prednisolone.The patient had no observed acute or chronic side effects for four years following treatment at the time of publication. An in vitro assay performed on the patient’s mononuclear peripheral blood cells did not demonstrate altered vulnerability to Mafosfamide and hence authors concluded that the 11778 mutation did not clinically change cellular response to cytotoxic therapy. The second case involved use of intrathecal methotrexate for treatment of acute lymphoblastic leukemia in a three-year-old patient. Marked leuko-encephalopathic changes were observed on brain magnetic resonance imaging but measured language skills remained stable. No visual impairment or disease conversion as a consequence of therapy had been reported by the authors. It is interesting that methotrexate in this case did not cause conversion particularly given its folate inhibition has been shown to result in a severe optic neuropathy thought to be mediated by mitochondrial dysfunction, even resulting in similar visual field deficits as LHON in one case report.To our knowledge, and as noted by other studies, there are no documented cases of chemotherapeutics resulting in LHON conversion and blindness.
The relative safety of chemotherapy in LHON may be bolstered through the use of adjunct antioxidant treatments. Our patient was treated with high dose Vitamin C based on evidence of faster visual recovery for LHON patients noted in one study for those treated with Idebenone, Vitamin B2 and Vitamin C. Some studies have shown improved biochemical marker profiles, compound muscle action potential amplitudes and motor performance in rats with cisplatin induced neuropathy treated with Vitamin C. However, the role of chemoprotective agents more generally in mitigating the neurotoxicity of platin based chemotherapy agents remains controversial, with insufficient evidence to support routine use. There have been traditional concerns that treatment efficacy may be compromised by antioxidant activity, although this has not been supported in the literature as found by one systematic review. However, there could perhaps be a greater role for antioxidants in patients with pre-existing congenital neuropathies such as LHON who are undergoing cytotoxic therapy.
We would argue that LHON is not an absolute contraindication to use of chemotherapy. The incidence of neuropathy associated with a specific chemotherapy drug does not appear to increase the risk of LHON, and instead selection should be based on risk of mitochondrial effects. This case demonstrates a further example of a case of hereditary optic neuropathy without conversion following exposure to cytotoxic therapy. We would propose the need for further studies to assess the safety of chemotherapeutic regimens in these patients to prevent an entire cohort of individuals from being excluded from potentially efficacious lines of treatment which may not necessarily pose the risks previously thought.