Yearly systematic and comprehensive examinations of the authors’ very large 11778 LHON pedigree allowed us to follow the natural history of this optic neuropathy with a large number of clinical, psychophysical, and laboratory measures. Three unexpected findings are described. First, affected patients demonstrated small deteriorations of their visual impairment. Second, carriers, who had no symptoms, did often demonstrate occult or subclinical disease. Third, visually unaffected carriers were observed going through the process of conversion to affected status. The classic description of LHON is as an all-or-none phenomenon whereby a few subjects suffer sudden and catastrophic monophasic visual loss.1,18
Yet, all three findings of the present study speak to the impression that LHON may represent a low-grade constant compromise of retinal ganglion cell function.
Many of the LHON carriers showed subclinical abnormalities. Focal edema was often seen involving the arcuate nerve fiber bundles, and this corresponded with areas of relative paracentral or arcuate scotomas on HVF testing. There were significant differences in color vision and contrast sensitivity between carriers and controls. The ONHC of mfERG data showed depressed paracentral responses and abnormal interocular asymmetries.
In both of the cases described here, peripapillary NFL swellings associated with mild microangiopathy at the superior and inferior poles of the optic disc were found on routine screening. GDx confirmed the NFL swelling. There were also mild central depressions as noted on HVF testing. These signs became more obvious the next year. In case 1, a paracentral scotoma was noted on frequency-doubling technology. The patient went on to have subacute loss of vision in one eye, followed months later by loss of vision in the other eye.
It is interesting to consider the progression of the subclinical signs, before the onset of acute visual loss in the conversion cases of LHON. However, it should also be noted that the same subclinical signs sometimes waxed and waned in other members of the pedigree. In the present case, we observed a march from focal nerve fiber layer swelling (especially at the superior and inferior poles) to an associated microangiopathy, then to central or paracentral mild visual field depressions, and then PMB thinning observable by fundus examination as well as by GDx. Finally, this buildup ended in severe subacute visual loss. Further NFL thinning and optic atrophy followed. These subclinical findings and their crescendo before the threshold of permanent and dramatic visual loss may provide important clues to the underlying pathophysiology.
Three intriguing disconnects are noted. The first is the temporal difference between the first subclinical signs and later visual loss. The second divide is between structure and function, as often the NFL swelling did not associate with visual loss. The third is a spatial disconnect. The most obvious NFL losses seen were in the inferior pole in the absence of arcuate scotomas but in association with relative central scotomas that anatomically should reflect PMB defects.
Recently, using OCT, a similar combination of changes in the NFL of LHON patients has been reported.30,31
The investigators describe in LHON-affected patients a stage of initial swelling of the NFL and then later a dramatic thinning of the temporal fibers. They also note that in LHON carriers, a statistically significant increase in NFL thickness can be seen by OCT.
These three disconnects suggest that structural changes need not directly reflect the primary pathology of LHON. Instead, NFL swelling may reflect compensatory effects such as the accumulation of mitochondria. Such aggregations of mitochondria have been described in several mitochondrial diseases, including LHON muscle.3
As explanation, we suggest that under duress, some of the nerve fibers adequately compensate by swelling with mitochondria, whereas others fail to do so, lose function, and eventually atrophy. Other changes, such as microangiopathy, may reflect the elaboration of trophic factors, such as vascular endothelial growth factor, by distressed neurons.
The first morphologic changes may reflect a wave of compensatory effects that may delay or even prevent the pathophysiology from reaching a critical threshold. However, once this threshold is reached, a cascade of decompensation occurs. This period of balance near the tipping point in LHON may be long, lasting many months. However, once the threshold is crossed, there may follow fairly acute losses of visual function.
This unparalleled opportunity of following over 300 patients with the same mtDNA mutation for LHON over a course of 5 years permitted us to observe subtle as well as dramatic evidence of the disease. Carriers frequently demonstrated manifestations of optic nerve impairment. The subclinical disease documented reflects a low-grade compromise that may often be compensated for. However, decompensation, often after a period of progressive worsening of visual function, may lead to dramatic impairments that mark the conversion from carrier to affected status in LHON. Further quantitative and objective measures performed in a very large number of well-characterized and homogenous cases of LHON can test the hypothesis of pathophysiology and, ultimately, lead to a rational and effective means of treatment.