Extreme vision loss
Undetected toxic batches of PFO and related products cause extreme vision loss
The current EU and International Standards Organisation’s (ISO) approved procedures for determining the safety of medical devices used for vitreoretinal surgery may need to be re-evaluated, according to J Carlos Pastor MD, PhD, IOBA (Eye Institute), University of Valladolid, Valladolid, Spain.
“Perfluoro-octane has been used for many years, with an apparent safety. But cases of acute toxicity related to three different products have been reported in 2013, 2015 and 2016. We do not know the exact reasons, but what is important is that the final and finished product is completely safe and that is achieved by performing appropriate cytotoxicity tests,” Dr Pastor told EuroTimes in an interview.
The cases included seven in Chile and four patients in Spain who underwent surgery with the PFO product, Meroctane (Meran), produced in Turkey, and 117 cases in Spain following surgery with AlaOcta PFO (Alamedics), produced in Germany. There were a further four cases with patients who underwent surgery with Bio Octane Plus – a mixture of 90% PFO and 10% perfluorohexyloctane produced in India – as an endotamponade (Pastor, J. C. et al., Retina. 2017 Jun;37(6):1140-1151).
Toxicities varied between patients but were commonly characterised by low visual acuity the day after surgery, optic nerve atrophy and acute retinal necrosis, sometimes leading to retinal holes and relapse of retinal detachments, and retinal vascular occlusion.
In the cases involving AlaOcta and Bio Octane plus, Dr Pastor and his associates were able to identify the cause in the majority of cases as the presence of contaminants in the PFO preparations. The toxicity of the products was not detectable by the indirect testing approved by ISO International Standards, but was detectable by a direct testing means developed at the IOBA institute.
With the cases involving a contaminated batch of Meroctane, the investigations carried out by another group were unable to identify the cause of the problem, and did not review cytotoxicity testing.
DIRECT TESTING VS INDIRECT TESTING
Dr Pastor noted that the independent testing facility that originally tested the contaminated AlaOcta batches used a technique in which cell cultures are placed in contact only with culture media extracts from PFO, an approach currently deemed acceptable by the ISO. But PFO is not directly tested since its toxic derivatives are immiscible in water and therefore also in culture media. The contaminated batch of Bio Octane Plus was tested using an agarose overlay method, in accord with ISO 10993 protocols.
“Both tests were indirect and both tests complied with the ISO norms, but it is obvious that they were unable to detect the toxic batches,” Dr Pastor said.
The IOBA group therefore has developed a direct contact method, using cultures of retinal cells of human origin (ARPE-19), which is capable of detecting toxic lots that current standard testing procedures might miss.
Using this method, they were able to identify toxic batches in which chemical analysis revealed the presence of two hydroxyl compounds, an acid and an alcohol, and benzene derivatives as the cause of acute toxicity in the case of the contaminated batches of AlaOcta (Retina 2017; 37:1140-1151). In the contaminated Bio Octane Plus batches, bromotributyl stannane was present at levels several-fold higher than is necessary to induce severe retinal toxicity. Yet to be determined are the how the toxic agents came to be in the PFO products.
“Information coming from the companies is very limited. Alamedics went bankrupt and has disappeared. We have tried to contact Biotech Vision Care, but they have not responded yet. We have identified the toxic substances but because we do not have information on the manufacturing process we are not sure where the primary problem is located,” Dr Pastor noted.
Non-complicated retinal detachment, 10 days
after surgery. Almost 50% of the vitreous
cavity still filled with gas. Retinal tissue
appears whitish and some haemorrhages cover
the posterior pole. Patient is in amaurosis
since the day of surgery
At present, the IOBA team is collaborating with the European Health Authorities through the Spanish Agency of Medicine and Medical Devices (AEMPS) to introduce modifications in the ISO norms regarding the cytotoxic tests, to promote the use of direct testing methods and eliminate the use of indirect testing methods.
“Unless this change is achieved, and implemented, companies cannot be sure what they will have to do in the area of safety.” Dr Pastor said.
The safety of PFO will also be the topic of a working group meeting during the EURETINA congress in Vienna, said Sebastian Wolf MD, Bern University Eye Clinic.
“This was not only a Spanish problem. There have been cases reported in Switzerland and Germany using the PFO from the same company. An independent working group meeting during EURETINA will discuss how testing of these substances can be improved. This group is an interest group independent from EURETINA, but we support them.
“Currently, it is quite easy to obtain CE mark for these substances, probably too easy. I think there is now a new European regulation for all medical devices (like PFO). These may prevent such toxicity problems in the future, but we have to examine the toxicity test on an expert panel. I think it would be very helpful to have a registry like the EUREQUO for reporting such problem,” Dr Wolf told EuroTimes.
J Carlos Pastor: firstname.lastname@example.org
Sebastian Wolf: Sebastian.Wolf@insel.ch