Ed Snow is out jogging with his friend Adam, and Adam discusses his marriage counseling with his wife. Ed admits he didn't get much sleep, but insists that things are fine with his wife, Elyse. Adam doesn't believe him, but Ed says that they work things out. When Adam wonders how often they have sex, Ed says that they have enough, and Adam figures he's weak because they had sex that morning. When Ed gets home, he calls out for Elyse and gets no response. He checks on her and discovers that she's barely able to wake up. She tells Ed to call in sick for her, but he says she's been sleeping for almost three days. When he tries to get her up, Elyse slaps him and then realizes something is wrong with her.
Cameron brings the case to House, who suggests that it's clinical depression. She doesn't believe it, and notes that the previous doctors didn't want to subject themselves to House by bringing it to his attention. He notices that Elyse was unusually irritable, but is more interested in why Cameron took the case. She doesn't answer, and he admits that her interest in the case interests.
In differential, Foreman dismisses the case as hypersomnia brought on by depression. Chase suggests parasites and Cameron notes that Elyse has never been out of the U.S. House suggests a tumor, but Foreman figures someone would have noticed it. However, House orders tests anyway.
At the clinic, House meets with a pre-school teacher, Samantha, who is complaining of shortness of breast. He discovers that she's had breast implants as a gift for her husband, and is duly impressed. He realizes that her problems might be related and calls in Dr. Wilson.
Foreman and Cameron meet with Ed and explain to the Snows about their tumor theories. They run her through the MRI to confirm.
Wilson is duly impressed with Samantha's breasts. House insists that she did it for herself, and notice that Wilson is wearing a new tie. When Wilson insists his wife picked it out as a gift, House notes that Wilson's wife hates that color and figures he's looking pretty for someone at work. Cuddy comes in and points out that it doesn't take two department heads to handle the case.
The team informs the Stones that there were no signs of a tumor. Elyse complains that she's not feeling well and then has a seizure. Later, they test her brain function and bring in Wilson. He suggests breast cancer and Cameron confirms that Elyse's mother died of breast cancer. They explain to Ed that breast cancer can cause the body's antibodies to be thrown off-track and attack the brain. Removing the breast tumor will eliminate the problem.
As Cameron runs breast scans, she tries to reassure Elyse. Elyse notes that her mother was the same age when she died, and explains that she and Ed have been trying for a child for the last year. Cameron tells her that a lot has changed since her mother's death and not to give up. The team examines the scans and find nothing, but Wilson insists that it could be hard to find, and it may not even present. House says to treat the symptoms and ignore tumor until it gets bigger. He tells them to check out her place of work and sends Foreman. Afterward, Foreman wonders why House is riding him. House admits that he is, but doesn't offer an explanation.
Foreman checks out the restaurant where Elyse prepares roasted meats and gravies. The head chef insists that his restaurant is clean and they don't use cleansers or pesticides, and says that no one else is ill. As he goes, Foreman notices that they prepare rabbit.
As Cameron checks on Elyse, Elyse wonders if she has better things to do and asks if she's in a relationship. Elyse talks about how Ed threw her towels out the windows after he threw up on them during a freshman party. She complains of neck pains and then notices a skin rash on her arm and starts itching. As Cameron goes to get some cream, Elyse hallucinates bugs crawling out of her arms and panics.
Foreman administers sedatives and Wilson confirms that hallucinations are consistent with his diagnosis. House suggests that she has an infection, but Foreman says that they've ruled out everything else. In response, House suggests she has African sleeping sickness, which fits the symptoms. Foreman confirms that she didn't have a transfusion and has never been to Africa, but suggests that Elyse's restaurant serves rabbit and she might have rabbit fever. However, Ed didn't notice the accompanying hacking cough. House admits it's the best they've got and congratulates Foreman, then notes that's why he rides Foreman. He then goes into his office and turns on the TV.
The team runs tests and Foreman wonders what House meant. Cameron suggests that they treat for both, but both treatments are dangerous.
House finishes watching his soap opera as Wilson comes in, and asks who he's dating. Wilson continues to deny he's dating anyone, but House figures it's someone in the hospital. Under pressure, Wilson finally admits that he had lunch with a nurse under pressure. Cuddy comes in with Samantha's test results, which turned out normal. However, House notices something wrong. He goes to see Samantha at the clinic and tells her that her EKG shows a reduced heart rate. When she wonders what's going on, House explains that her husband has been putting his beta-blockers in her oatmeal to decrease her sex drive, so he doesn't have to have sex with her. When Samantha wonders what to do, House starts to tell her to have an affair and then gets an idea.
House goes to see the team in the lab and explains that sleeping sickness can be transmitted by blood. Since Ed hasn't been to Africa, she must have cheated. Cameron insists they're devoted to each other, and House suggests that they're overcompensating. He tells Foreman to ask Ed and Cameron to ask Elyse. Cameron confronts him outside and asks if he doesn't trust her, and he says that he pulled her medical records after she had issues over the baby deaths.
Foreman lays it out for Ed, while Chase ends up talking to Elyse. Both of them insist that they didn't cheat on their spouse, despite the fact that Elyse will die if they don't learn the truth. When he finds out, House crosses off sleeping sickness, proscribes for Foreman's diagnosis, and leaves for the night. Cameron administers the new treatment but Elyse displays memory problems and then goes into a coma.
The next morning, House concludes that they're back to sleeping sickness, and Ed or Elyse lied. He goes in to check Elyse's lymph glands and tells Ed that she has sleeping sickness. Ed says he hasn't had an affair and he trusts Elyse, but House warns that the treatment has a 10% fatality rate if she doesn't have the illness. He needs Ed's written consistent, and warns that he shouldn't do it... unless he allows for the chance that Elyse was unfaithful even once. Ed admits that he isn't sure, and House begins the treatment.
Foreman and Chase administer the extremely painful treatment, and Cameron gives the next series of injections. Ed wonders if Elyse knows he's there, and admits he doesn't want her to get better because that would mean she cheated on him. He asks Cameron if that makes him a terrible person, and she tells him that it does.
Wilson notes that House is treating Elyse based on the fact he figures that she's having an affair. He insists that he isn't having an affair, but House warns that he eventually will. Going into the lab, House finds Cameron crying as she recalibrates the centrifuge. She admits she told Ed that he was a jerk, and explains that she fell in love in college and got married, It lasted six months, after he died when cancer metastasized in his brain. House figures that isn't the entire story, and points out that she had to know he was dying before she got married.
Elyse's condition worsens and Chase warns that the treatment is killing her faster than the hypothetical disease. They tell Ed, who begs Elyse not to die. The team watches as Elyse reaches out to touch her husband as she starts to recover.
Later, Cameron watches the couple and Foreman tells her that Elyse will be okay. However, Ed takes his bags and leaves, now convinced that Elyse slept with someone. Cameron goes after him and wonders what he'll do, and that Elyse loves him. Ed simply walks away.
House comes to see Elyse and tells her that they have to notify the man she had the affair with. He wonders why she lied despite the risks, and says that they all make mistakes... and all pay a price.
Once they have the name, Cameron goes to the house next door to the Snows, and asks the boy sitting outside where his dad is. Adam comes out and Cameron goes to give him the news.