From Cholesterol Anesthesia to Anticonvulsant Potatoes and Hepatic Encephalopathy
by Steven Curry, M.D.
Banner – University Medical Center Phoenix
University of Arizona College of Medicine – Phoenix
Another Thanksgiving has come and gone, this year complicated by COVID-19. Last year at this time I discussed endozepines, idiopathic recurrent stupor and hepatic encephalopathy. I examined the history of endozepine-4 and its relationship to idiopathic recurrent stupor, which culminated in the large idiopathic stupor outbreak in Tuscany and the subsequent discovery that the outbreak appeared to be explained by lorazepam. At the time of the writing, I did not have great details concerning the outbreak and asked that anyone who may have more details to please fill the rest of us in. Thus, we welcome Quinn Eastman.
Quinn works at the Emory University School of Medicine and is a superb science writer and maintains the Lab Land blog. Quinn’s interests have focussed on hypersominia and related sleep disorders. In working on an upcoming book on these topics, Quinn has researched the Tuscany outbreak, interviewed some physicians involved, and has provided a wonderful summary, below. In my original post, I noted that some persons had hypothesized the outbreak was due to young persons testing out illicit lorazepam on some elderly citizens. Quinn’s excellent summary quickly disproves this conjecture and takes us from the origin of the outbreak to criminal investigations and court actions. Please read/review the original post and then the appended summary of the Tuscany outbreak. And keep an lookout for Quinn’s book. I’ll broadcast an announcement when it is released.
The downfall of “idiopathic recurring stupor”
by Quinn Eastman
In the spring of 1997, residents of Camigliano, a community in Tuscany about 10 kilometers east of Lucca, began falling asleep under mysterious circumstances. One by one, seven people entered a trance-like lethargic state, typically lasting 10 to 20 hours. The strange somnolence affected a woman in her 80s more than 10 times, while affecting her neighbors and relatives between one and five times. The signs of onset were similar: dizziness, loss of coordination, sometimes nausea, and then sleep. Some people could briefly respond to questions or even eat, but then returned to slumber. Upon waking, they did not remember what happened. According to newspaper reports, one woman was folding laundry on her balcony, when she felt her head becoming heavy. She lost her balance and her husband had to help her inside. Another woman zonked out while driving, and her car ran into a wall, causing minor injuries.
In the first episodes in March and April, the woman in her 80s was taken to a hospital in Lucca. Tests such as brain MRI, electrocardiogram and toxicology did not explain what had happened. Then the weird sleepiness started to hit others. The first patient’s daughter lived a few kilometers away, but she was struck by sudden somnolence when she was driving back from visiting her mother. By the end of August, a doctor named Attilio Favilla, who had cared for the sudden sleepers, became alarmed and asked the local health department (Unita Sanitaria Locale or USL) for help.
The public health investigation centered on a few houses around a courtyard garden, a pleasant spot decorated with begonias and geraniums where a group of neighbors socialized. Officials first looked for an environmental cause, testing wells where people in the community obtained their water. They quizzed residents about their eating habits, and inspected the paint and carpet in their homes and the gas lines in their kitchens. Suspicion fell upon a mobile telephone tower that had recently begun operation. An environmental advocacy group demanded the shutdown of nearby high-voltage electric lines. Nothing emerged that could account for the “sleeping sickness.”
An enterprising reporter for regional newspaper Il Tirreno published the first story on the phenomenon in September 1997. At first, newspapers did not print affected individuals’ full names. They were described collectively as the “lethargics” (letargici). By September 24, Camigliano residents were complaining that they were under siege from crowds of reporters, and that a television crew had barged into someone’s house.
All the media attention brought an intervention. Giuseppe Plazzi, a neurologist from the University of Bologna, arrived in the second half of September. The head of his department, Elio Lugaresi, charged Plazzi with evaluating the sudden sleep phenomena and assisting the USL investigators. Plazzi had been on vacation with his family when Lugaresi called, telling him to buy a newspaper to catch up and then go to Tuscany.
Plazzi followed orders, bringing along a colleague, pharmacologist Roberto Riva. When they showed up, a television crew was already interviewing Camigliano residents. They were eager to have doctors examine them, Plazzi recalled in an interview. Fortuitously, a 51-year old woman fell into a lethargic state while the doctors were there.
In his account, Plazzi wrote that the woman lay on a couch “motionless, as if her eyes had crossed the eyes of Medusa.” She was breathing regularly, but didn’t respond to shaking. The woman was taken to the Lucca hospital, where Plazzi was able to survey the EEG patterns made by her brain while she was asleep. He detected a characteristic high frequency pattern suggesting that she was under the influence of benzodiazepines.1 Plazzi and Riva gave her flumazenil, which quickly woke her up.
A possible interpretation of events was that the sudden sleepers were under the influence of benzodiazepines. However, affected individuals swore that they had not knowingly taken sleeping pills. Their doctor and local pharmacists confirmed their assertions. When blood samples from Camigliano were analyzed in Bologna, Lugaresi announced a tentative diagnosis: idiopathic recurring stupor (IRS). Lugaresi’s pronouncements carried weight – he was an internationally known researcher who had studied conditions such as sleep apnea and fatal familial insomnia.2
When Lugaresi’s team analyzed the samples from Tuscany chromatographically, they spotted “endozepine 4,” which they had seen before in their IRS patients. Lugaresi told reporters: “We are 99 percent sure that the substance found in this first analysis is also present in the blood of the other eight people in Lucca.”
Lugaresi’s announcement spurred more environmental fact-finding, and more speculation. In Camigliano, just outside the homes of the lethargics, the USL set up two mobile laboratories for monitoring air quality. Public health officials proposed that sleepers’ bodies might be metabolizing pesticides from a nearby farm into endozepines. Sudden sleep incidents continued in September and October.
At the end of October, the USL declared its intention to evacuate the lethargics from their homes for a few months. The goal was to test if the cause of the incidents was environmental. The idea came from the Lucca public prosecutor’s office, which told news organizations its interest was based on possible environmental pollution. At the beginning of November, several residents cleared out of their houses and went to stay with friends or relatives, saying they felt “like earthquake victims.”
Meanwhile, Lugaresi’s team in Bologna made a transition to better tests. They figured out that “endozepine 4” in samples from Camigliano’s sudden sleepers was in fact lorazepam, the widely available anti-anxiety and insomnia drug. In November 1997, Lugaresi and the USL broke the news together. There was no need to hunt for the cause of an exotic new disease. Instead, prosecutors proposed that a sneaky person may have introduced the drug into sudden sleepers’ food or drinks. They reviewed more than 30 sudden sleep incidents, trying to determine whether someone had a chance to act covertly.
By the middle of November, charges were announced against a married couple who were neighbors of some of the lethargics. At one point, the female suspect was supposedly hit by the lethargy herself. She had looked after the initial victim, cooking and performing other household tasks for her. Her husband, a paper mill worker on disability, allegedly had provided lorazepam from his own supply. Although it appeared that no physical harm had come to them, the sudden sleepers could have had more serious car accidents, choked on food, or fallen down stairs. A fatal overdose of lorazepam is difficult to achieve by itself, but is more likely if the drug is combined with alcohol, or given to an elderly person with existing cardiac or respiratory troubles. Several of the lethargics were in their 70s or 80s. An Il Tirreno headline summarized their reaction: “Anger and dismay after seven months of hell.”
Two scientific communications tell the Bologna side of the story. In a follow-up letter to their 1998 Brain paper, Lugaresi, Plazzi and colleagues reported they had found lorazepam in the Camigliano samples using liquid chromatography-mass spectrometry.3,4 They concluded that an endozepine origin for other IRS cases “should be considered as still unproven.”
A second exchange in The Lancet added more heat than light.5 Prompted by a teasing letter from an anesthesiologist in Lucca, the Bologna doctors claimed that they had always been suspicious of the Camigliano IRS cases:
. . . despite the negative toxicological findings our instinct told us to look out for benzodiazepine overdose, so we carried on sniffing around for these, as well as the endozepines, in the patients’ plasma samples. We finally managed to identify lorazepam . . . Naturally, we informed the magistrate, but otherwise we kept our findings strictly to ourselves, to avoid hampering early legal investigations, which subsequently led to the offenders—who appeared to have been poisoning their neighbours—being accused.
Evidence presented against the accused at trial was circumstantial, according to both newspaper accounts and a later review at the University of Bologna (kindly provided by Francesca Ingravallo). Nobody ever saw the suspects introduce pills or drops into the victims’ food or drink, and it wasn’t clear that anything had been taken from the victims during their impaired states. One of the victims told prosecutors in court she once noticed “strange bubbles” on the surface of a dish of soup prepared by her neighbor. This testimony is questionable, because of the disruptive effects of lorazepam on memory. The case against the main suspect was mainly that she was present at the right times, and her husband was supposed to have supplied the drugs. Prosecutors speculated that she may have been motivated initially by gifts from the victims, by the opportunity to receive attention, and later, expenses paid for television appearances.
In 1999, the couple was acquitted by the Lucca court. In the Italian justice system, in contrast to the United States, prosecutors have the option of appeal. They were able to convict two years later. According to Il Tirreno, the female suspect lost her job and had to move in with her daughter. In 2002, the case eventually reached the Italian Supreme Court, which cited the lack of hard evidence and threw it back, leading to the female suspect’s exoneration in 2003.
Over the years, the Bologna team has been able to clear up most of the IRS incidents. Riva said in an email: “The issue is delicate. In some of these cases, we also identified those who periodically poisoned the subjects and why. In almost all cases, there was admission of responsibility. As the perpetrators were close relatives, the issues resolved without the intervention of the judiciary, and the episodes have not reappeared.”
Currently, idiopathic recurring stupor appears to have been a mirage. In a 2014 paper published in Sleep, members of the Bologna group confirmed that samples from their IRS cases contained synthetic benzodiazepines.6 They concluded: “Spontaneous IRS is therefore an unproven and indeed questionable entity.”
Hope that everyone had an enjoyable, safe and wonderful Thanksgiving. Please give us some feedback on Twitter, or comment below.
- 1.Grözinger M, Kögel P, Röschke J. Effects of Lorazepam on the automatic online evaluation of sleep EEG data in healthy volunteers. Pharmacopsychiatry. 1998;31(2):55-59. doi:10.1055/s-2007-979299
- 2.Lugaresi E, Medori R, Montagna P, et al. Fatal Familial Insomnia and Dysautonomia with Selective Degeneration of Thalamic Nuclei. N Engl J Med. Published online October 16, 1986:997-1003. doi:10.1056/nejm198610163151605
- 3.Lugaresi E. Endozepine stupor. Recurring stupor linked to endozepine-4 accumulation. Brain. Published online January 1, 1998:127-133. doi:10.1093/brain/121.1.127
- 4.Lugaresi E. Suspected covert lorazepam administration misdiagnosed as recurrent endozepine stupor. Brain. Published online November 1, 1998:2201-2201. doi:10.1093/brain/121.11.2201
- 5.Riva R, Lugwesi E, Fanelli R, Mennini T, Chiabrando C. Spinning more yarn: endozepine. The Lancet. Published online April 1998:1138. doi:10.1016/s0140-6736(05)79430-7
- 6.Plazzi G, Rye D, Vignatelli L, Riva R, Lugaresi E. Idiopathic Recurrent Stupor: Munchausen by Proxy and Medical Litigation. Sleep. Published online January 2014:211-211. doi:10.5665/sleep.3342