Aboard a cruise ship, amidst the festive atmosphere, 53-year-old Silvano, a man known for his elegance and tuxedo-clad charm, noticed something unsettling. Perspiration drenched his shirt as he danced, and a mirror revealed pupils constricted to mere pinpricks – the same chilling stare that had preceded the mysterious decline of his father and sisters.
This was no mere ailment; it was the dreaded family curse manifesting. Silvano knew the horrifying path ahead: tremors, impotence, constipation, and the ultimate terror – the vanishing of sleep. Months of relentless insomnia, a waking nightmare leading inexorably to death.
“I’ll stop sleeping, and within eight or nine months, I’ll be dead,” he declared to Pietro Cortelli, a doctor at the University of Bologna’s sleep unit, where he sought diagnosis, devoid of any illusion. He even drew his family’s genealogical tree, tracing the curse back to the 18th century, each generation marked by the same tragic fate.
True to his grim prophecy, Silvano passed away within two years, bequeathing his brain to science, a final act of hope to illuminate the darkness of the disorder that haunted his lineage.
The enigma of Fatal Familial Insomnia (FFI) – what transpires within the minds and bodies of its victims? Researchers are only now beginning to unravel this mystery, edging closer to potential treatments for this devastating condition. However, FFI’s genetic nature casts a long shadow, raising profound ethical questions: if your DNA held the secret to sleepless oblivion, would you want to know your destiny?
Tracing the Origins of a Sleepless Curse
Silvano’s family, shrouded in silence for generations, eventually shared their story with writer D.T. Max, whose book, The Family Who Couldn’t Sleep, paints a poignant picture of a family living under the genetic sword of Damocles. Max’s quest to find “patient zero” led him to an 18th-century Venetian doctor who succumbed to a prolonged, paralyzed stupor. The affliction then surfaced in his nephew, Giuseppe, and cascaded through generations – Angelo, Vincenzo, their descendants, and finally reaching Silvano’s father, Pietro, a casualty of World War II.
Fearful of tempting fate, the family rarely spoke of the illness. This changed in the 1980s with Silvano’s symptoms. His niece’s husband, Dr. Ignazio Roiter, a scientist, urged Silvano to consult Elio Lugaresi’s renowned sleep clinic in Bologna, where Dr. Cortelli worked.
Together, they embarked on a quest to decipher the disease. Though their efforts couldn’t save Silvano or other affected family members, rigorous investigations unveiled the culprit: a misfolded brain protein called a prion, a consequence of a subtle genetic mutation. These prions, inexplicably, begin to multiply in middle age, accumulating and poisoning neurons.
The prion connection linked FFI to Creutzfeldt-Jakob disease (CJD) and Mad Cow Disease, prion diseases then under intense scrutiny. However, unlike CJD, which creates a Swiss cheese-like appearance on the brain’s surface, FFI zeroes in on the thalamus, a walnut-sized structure nestled deep within the skull. In Silvano’s brain, the thalamus appeared ravaged, as if riddled with wormholes.
Years of research revealed the thalamus’s crucial role in orchestrating autonomic bodily functions: temperature regulation, blood pressure, heart rate, and hormone release – the body’s essential housekeeping. Thalamus malfunction throws this system into disarray, akin to a home with a broken furnace, burst pipes, open windows, and blaring alarms. This explains the sweating, constricted pupils, impotence, and constipation.
The Thalamus: Switchboard of Sleep and Consciousness
This autonomic chaos contributes to the intractable insomnia. The body, unable to regulate itself for rest, remains in a perpetual state of alert. “If the sympathetic nervous system is unbalanced, of course you’ve got insomnia,” explains Dr. Cortelli.
Furthermore, the brain’s sleep rhythms are disrupted. Normal sleep cycles through REM (rapid eye movement) and deep “slow wave” sleep. Slow wave sleep, characterized by low-frequency electrical oscillations across the cortex, quiets conscious activity and performs vital maintenance, such as memory consolidation. The thalamus is the conductor of these rhythms. In FFI, this “dimmer switch” fails. Patients remain perpetually “on,” never achieving restorative deep sleep, as demonstrated by Angelo Gemignani at the University of Pisa.
The closest FFI sufferers get to sleep is a mindless stupor – a twilight state, neither fully asleep nor awake, where they may unconsciously act out daily routines. Dr. Cortelli believes this is a fragmented REM sleep remnant, a kind of dream enactment. He recalls Teresa, a hairdresser before the disease, mindlessly mimicking hair combing.
A Glimmer of Hope: Daniel’s Prolonged Battle
Amidst this bleak prognosis, one patient, Daniel (name changed for privacy), offered a sliver of hope. Psychologist Joyce Schenkein encountered Daniel through a 1990s radio chat line. “He was very clever – a brilliant guy, extremely funny,” she recalls, leading to a long-distance friendship.
Years later, Daniel’s communication became confused. “At some point, he said ‘pardon me if I sound incoherent but I haven’t slept for five days,’” Schenkein recounts. Tests confirmed the FFI mutation. His mother had known of a paternal family illness but shielded him from the specifics. Worse, his was the rapidly progressing form.
Instead of succumbing to despair, Daniel bought a motorhome and embarked on a US road trip. “He was an adventurous spirit – he wasn’t just going to sit there and die,” says Schenkein. As symptoms intensified, he hired a driver, then a nurse, to navigate when he was too ill.
Daniel relentlessly pursued potential treatments – vitamins, exercise, anesthetics like ketamine and nitrous oxide, sleep medications like diazepam – seeking even fleeting moments of sleep. He even acquired a sensory deprivation tank, finding that even under anesthesia, minimal stimuli could shatter his fragile sleep.
Floating in the tank’s warm, salty embrace, he achieved four and a half hours of profound sleep. However, awakening brought terrifying hallucinations, a disorienting uncertainty of being alive or dead. He even tried electroconvulsive therapy, hoping for unconsciousness, but the severe amnesia rendered it impractical. Despite these efforts, relapses grew more frequent and intense. “When the symptoms reared themselves, he couldn’t do anything,” Schenkein says. “He could sit there without the initiative to move; he’d be frozen in time.” Eventually, Daniel succumbed to the disease.
The Promise of Doxycycline and Ethical Dilemmas
Although Daniel’s treatments weren’t a long-term solution, he lived longer than expected. Schenkein highlights research indicating slow-wave sleep facilitates cerebrospinal fluid cleansing of brain waste. By mitigating insomnia, perhaps Daniel facilitated this “clean-up,” slowing brain degeneration. With Italian neurologist Pasquale Montagna, Schenkein documented Daniel’s case, hoping to inspire research into life-extending measures for FFI patients.
“It at least opens the possibility to say that there is something we can do,” says Dr. Cortelli, though he cautions against generalizing from a single case. The Venetian family’s hope rests elsewhere. Lugaresi passed away, but Roiter and colleagues in Milan and Treviso are pursuing a potential cure: a clinical trial for doxycycline, a drug showing promise in preventing prion formation.
Doxycycline, initially an antibiotic, seemed to hinder prion clumping and promote their breakdown. A small trial on early-stage CJD patients showed those on doxycycline lived twice as long. However, a later trial with advanced CJD patients showed no benefit, suggesting timing might be crucial. Roiter’s team is investigating doxycycline as a preventative for at-risk FFI individuals, hoping to delay or prevent prion accumulation.
Setting up the trial involved ethical complexities. Genetic testing identified carriers, but many family members preferred not knowing their status, fearing constant anxiety. Therefore, 10 carriers aged 42-52 are receiving doxycycline, while 15 non-carriers receive a placebo, ensuring no participant knows their genetic status.
Without intervention, statistically, four of the carriers would likely develop FFI within a decade. If more than six remain disease-free, the trial will be deemed successful, potentially leading to broader doxycycline use.
The trial, however, is not without controversy. Dr. Cortelli opted out due to ethical concerns. Doxycycline’s side effects might reveal participants’ diagnoses, causing undue distress, despite planned psychological support. He also questions the drug’s efficacy warranting prolonged treatment, and points out that some mutation carriers live long lives regardless, possibly due to chance.
Despite these uncertainties, the family’s willingness to participate is understandable. They are gambling on hope, seeking to overturn a centuries-old genetic death sentence. Silvano’s niece’s nightly checks on her mother, the “spy in her own home,” illustrate the constant fear. If doxycycline works, it could end this nightmare, ushering in a future where sleep is a solace, not a harbinger of doom.
