The work of one dedicated physician can sometimes shed light on the most misunderstood or obscure disorders that afflict us. The elucidation of a rare condition, centuries-attributed to madness, really fell into the hands of one brilliant doctor in Northern Italy on a personal crusade for answers.
Ignazio Roiter, an Italian physician, was the first to identify fatal familial insomnia (FFI) in 1979. The road leading to this identification started with the mysterious illness he witnessed one of his wife’s relatives fall victim to; she exhibited agitation and paranoia, progressing night-by-night to longer bouts of total insomnia, until the woman could not sleep at all. Finally, she became mute, and sleepless entirely, losing dramatic amounts of weight before dying twelve months after her initial symptoms began.
Six years later, the woman’s sister began experiencing the same symptoms and ultimately died in the same fashion. A realization woke in the mind of Dr. Roiter, and as he traced the family tree back through generations, a clear and intimidating pattern began to rise to the surface.
Thirty other relatives through the generations had succumbed to a premature death after bouts of neurological symptoms and unending insomnia. There are now approximately one hundred known family lineages that are susceptible this heritable condition.
In 1997, the work of another scientist finally identified the cause of this disorder. It was classified as a transmissible spongiform encephalopathy, more commonly known as a prion disease, affecting the thalamus of the afflicted. Prions are proteins that are misfolded, due to a mutation in the prion-related protein (PRNP) gene, which begin to slowly induce the healthy proteins around them to transition into nonfunctional, misfolded proteins. Occurring in neural tissue, this has devastating effects–and all disorders of this type are incurable at this point in our medical understanding.
The clinical presentation is uniquely horrifying, with patients experiencing disease progression for anywhere between six and thirty-six months. One common thread unites them all: a progressive inability to sleep, untouchable by medication.
Take the case study of a fifty-year-old female who presented to a clinician with complaints of sleep disturbances and changes in behavior, reporting that those symptoms had begun over a year prior. She had worsened over the course of that year, first developing involuntary movements of the hands, then involuntary movements of entire limbs. Her breathing was disordered during sleep, with snoring and shrill laryngeal noises. As time went on, she experienced a bout of transient global amnesia, which is a total loss of awareness and memory. In her case, this experience lasted six hours. Finally, she became unable to urinate and sweated profusely, as well as experiencing full nights without any sleep whatsoever.
Upon admission, the patient was fully conscious but confused and cognitively deficient, especially in spatial and situational awareness. The patient also had several lesions in brain scans, with the thalamus and brain stem being particularly affected. A litany of tests were performed, but one finding was particularly unsettling. Lurking in her cerebrospinal fluid were the mark of a horrible prognosis: 14-3-3 proteins.
The presence of this 14-3-3 protein is a near-certain marker of incurable prion diseases. 95% of Creutzfeldt-Jakob disease patients (commonly known as mad cow disease–another prion disorder) had 14-3-3 proteins circulating in the cerebrospinal fluid. However, this test is not without error, with only 50% of familial spongiform encephalopathy cases in the above-linked study having the presence of this protein type. For that reason, detection of the 14-3-3 protein in CSF should cause immediate suspicion of a prion disease, but the lack thereof should not deter the clinician from the possible diagnosis of fatal familial insomnia. It is only possible to truly diagnose prion diseases postmortem upon examination of grey matter brain tissue.
Two months after diagnosis of suspected fatal familial insomnia, the patient began to experience tremors and delirium, including crocidismus: an agitated, delirious picking of clothing and bed linens. At this point, she was experiencing total sleep deprivation, existing primarily in a semi-conscious state of agitation. After a total duration of twenty months, the patient finally died. Of those twenty months, the majority were spent in near-total sleeplessness. Each hour of sleep was fought for. Exhaustion was omnipresent.
This disease is brutal. The progression causes suffering to patients that is unimaginable to those who have not experienced the entire lack of sleep that occurs in the end-stages of this disorder. Patients try desperately to attain the sleep that is becoming a physical impossibility, their efforts increasing in futile desperation, with one patient in the middle stages purchasing a sensory deprivation tank, reporting that it was the only way for him to fight his way into sleep. But in the end, none of their efforts yield any leeway with this cruel condition. Most terrifying of all, it is not simply limited to those with genetic predisposition. Like many prion disorders, this condition has a spontaneous version; for unknown reasons, sometimes a healthy protein will choose to fold the wrong way in the brain of an non-predisposed patient. Sometimes, it’s impossible to predict who it will affect.
In spontaneous fatal insomnia (SFI), patients lack the genetic mutation seen in FFI. Healthy, non-predisposed people, walking around, living their lives, suddenly undergo a change that can happen to anyone, anywhere. There is no understanding surrounding why or how spontaneous prion disorders occur. Those with SFI have a marginally longer life expectancy, but it remains 100% fatal. The 14-3-3 protein is also a heavy diagnostic tool in SFI, but like its heritable version, only the biopsy of brain tissue can show the hallmark holes in thalamic grey matter that prove the presence of the prions.
The four stages of fatal insomnia are always near the same.
- Stage 1: The patient suffers from acute inability to sleep, worsening over the course of a few months. Often, lucid dreaming is reported, with waking psychiatric symptoms like paranoia, panic attacks, and phobia being a common presentation.
- Stage 2: This stage is the five month period in which increased respiration and blood pressure, alongside other sympathetic hyperactivity is reported. Insomnia in this stage continues to worsen, along with psychiatric symptoms, and hallucinations are often reported.
- Stage 3: This stage, lasting around three months, marks the beginning of total sleeplessness.
- Stage 4: The final stage, lasting around six months, continues with total insomnia with symptoms of rapid cognitive decline and dementia. Often, patients lose the ability to voluntarily move or speak. Death is the inevitable outcome.
Though the work of single, attentive physicians can often lead to the recognition and identification of disease, it often takes the collective efforts of the scientific community to work out cures for complex disorders such as this. Prion diseases were only identified in 1997, again discovered through the work of a single researcher, Nobel Prize winner Stanley Prusiner, and the young nature of the study of prions is evident in our relative lack of scientific understanding of their mechanism, pathology, and progression. It is an entirely new type of disease. And unlike viruses, bacteria, and fungi, these proteins are near impossible to destroy, surviving autoclaving, boiling, and disinfection, sometimes remaining potent enough on surgical instrumentation to survive years after they were transferred onto it, infecting the next patient on which the instrument is used. They contain no genetic information, they are near indestructible, and technically, their ability to ‘infect’ other proteins should be an impossibility.
It takes the work of many researchers to find clinical solutions to the cruelest and most puzzling disorders. With the work of physicians and researchers, the heritable version of fatal insomnia could be attenuated with genetic engineering, or maybe with increased understanding of the mechanism by which prions infect, effective treatments can be developed to prevent the deaths of the unlucky few who fall victim to the spontaneous version. This is an arena of pathology well worth intensive research. Though prion disorders are rare, the suffering they inflict is unimaginable, and the resistance of these curious pathogens to all modern disinfection makes them an invisible, lurking movie monster, impossible to ignore on the horizon of pathology.
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