My reply to the OP here is with the caveat that I am already sensitive in the first place to getting headaches and to seeing blurring and other visual artifacts in video games, just because of a light-sensitive medical condition I have.
However, some video games are more difficult for me to play than others in that respect: and with D2R, I have definitely been experiencing that its updated graphics are much more strain for me to play with, than it is for me to play D2 or D2R in its legacy mode.
I think that may be because the style that was chosen for D2R’s updated graphics has a very low-key colour-range and subtle shading and contrast, in-comparison to D2’s original graphics.
That style in D2R is nice to look at, and it arguably tries its best to be faithful to D2’s original colour palettes. So I hesitate to criticize it.
But I am nonetheless finding it more difficult to distinguish elements and visually process everything that is happening on-screen in Diablo with such a low-key style in D2R’s updated graphics, versus how easy it is to visually process everything when I am playing D2 with its original graphics.
That might not be noticeable right away when playing with such a low-key style in D2R’s updated graphics. But I think that it eventually causes a player more cognitive and visual strain trying to visually process everything in it over time; hence more headaches and eye-strain in the long run.
However, most of that issue I have been experiencing with D2R’s updated graphics is just when I am playing it in its default settings.
That is, I think that you can still do a lot to compensate for that issue in the video settings in D2R’s options, thanks to its settings there are also much more extensive and inclusive for people with visual conditions than I have seen before in video-games.
E.g. among other things I’d suggest to the OP here: Try reducing the amount of on-screen detail/clutter, and increasing the contrast and colour-intensity in D2R’s settings, just enough so that you can distinguish elements on-screen more easily.
Even if you aren’t colour-blind, also try each of the different settings for colour-blindness there, just to see if any of them make it less of a strain for you to play.
Besides those settings in D2R: Also try reducing the amount of blue light in your computer’s settings or in your monitor’s settings, because that part of the light spectrum in computer monitors is also known to cause headaches and migraines for some people, especially after extended screen-use.
Also beware that low frame-rates and monitor screen-flicker can be problematic for some people, even if the frame-rate and monitor flicker are so fast that it cannot be seen with the naked eye. So I would also keep your frame-rates as I as you possibly can so long as the animation is still smooth; and keep your monitor screen’s refresh rate as high as you can.
Last but not least: If you are playing D2R on the Switch, you can also get a blue-light-filtering screen protector for it. That might help, too.