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.