The first way you can lose a game as stated in the rules is "if you don’t have any available moving options during the Explore phase (e.g. the top card of the deck has no active value and the next card has no active value or is facedown). "

This scenario isn't really possible in the Core Set because the card missing a value on one of their sides never allows that situation to happen; an encountered Frenzied Flame immediately removes itself from the top of the deck and skips that turn's Explore phase.

However, Orzumal's Eye from the Knowtorious (2nd) Expansion is the first card that turns that first lose condition into a real possibility. It's deceptively dangerous because the card doesn't have the Skull Attribute since its ability can't directly lose you the game like Figments of Feragot or Feragot's Fortress can, but it can easily leave you with no available moving options resulting in an unexpected early game loss! So, delay your 2nd encounter with it until you're ready to survive its vortex and harness its power!

Note: Each subsequent even-numbered encounter with the whirlpool (4th, 6th, 8th, and so on) should be less and less dangerous since most cards in the deck will be faceup by that point in the game.