Dying to Sleep — The Waking Nightmare of Fatal Familial Insomnia
Insomnia can be problematic for many of us. It can make us more tired and irritable during the day. It can cause problems with attention and concentration and increased daytime somnolence (sleepiness).
If it becomes actual sleep deprivation there may also be various metabolic complications including a greater risk of developing obesity and type 2 diabetes.
There is a rare genetic condition, however, where the disruption to sleep is so severe that it becomes terminal.
It is known as Fatal Familial Insomnia (FFI) — and I think this may truly rank high on the list of the worst ways to die.
Those who develop it are almost literally thrust into a waking nightmare.
Thankfully I have never had to treat any patients with this disease in my medical career and I hope I never do.
A Few Quick Notes
I will try to make this article as brief as possible and would suggest if you find this interesting that you use some of the references to read up on this further.
This is simply too complex a topic to cover in any significant depth in a post like this.
If you want a more human centric and less clinical discussion I would recommend reading this BBC article — (I have included a small excerpt below).
There is also a book on the subject that various people have recommended to me (I haven’t read it yet):
I will also post a link to a Discovery Channel documentary I found on Youtube and a news report on a family suffering from the condition at the bottom of the post.
There is a BBC documentary too which I saw a number of years ago called “The Man Who Never Slept” but I have not been able to find it online — if you do find a link to it please let me know.
The Human Story — the Family “Curse”
The BBC article details the case of Silvano who developed FFI at the age of 53:
“Silvano was on a cruise ship when the family curse struck. An elegant 53-year-old with striking red hair who enjoyed wearing a tuxedo at every possible occasion, he tried to present himself with the poise of the film stars he admired. But while on the ship’s dance floor one evening, he was embarrassed to find that his shirt had become drenched in sweat.
Concerned, he examined himself in a mirror, only to find that his pupils had shrunk to two tiny black pinpricks. It was the same glassy-eyed stare that had afflicted his father and two sisters at the beginning of their mysterious illnesses.
He knew this was just the beginning. Tremors, impotence and constipation could follow.
But the most terrifying symptom would be the disappearance of sleep — almost total insomnia for months; a kind of waking coma that ultimately would end in death.
Silvano eventually referred himself to the University of Bologna’s sleep unit for further study, but he was under no illusions about the course of the disease.
“He said, ‘I’ll stop sleeping, and within eight or nine months, I’ll be dead,’” one of his doctors, Pietro Cortelli, told me in a phone interview.
“I said ‘how can you be sure?’ He then drew me his genealogical tree from the 18th Century, all by heart.” In each generation, Silvano could name family members who had succumbed to the same fate.
As Silvano had predicted, he died less than a couple of years later, but he left his brain to science in the hope that it might shed some light on the strange disorder that had plagued his family.”
It is the history of Silvano’s family that is covered in the book which I mentioned above (The Family That Couldn’t Sleep: Unravelling a Venetian Medical Mystery). One can only imagine how horrifying it must be to find yourself afflicted with this condition.
Describing it as a “curse” is truly apt.
The BBC article also covers the case of a patient known as Daniel who seems to have been one of the people to survive longest following the diagnosis of the disease.
I mention it because his case is also covered in a series of Medscape articles which you can find the first of here.
It seems he may have been able to extend his life and improve his quality of life using some novel methods which are covered in more detail in the article.
What we know about FFI
This is what is known at the moment about FFI. It has or is:
- Autosomal dominant genetic inheritance — this means you only need one copy of a faulty gene to inherit it. So if one of your parents has it (the single gene variant) you have a 50% chance of inheriting it. If either parent has 2 copies of the affected gene then the chance is 100%.
- Prion Disease — you may have heard of prions before — for the purposes of this article, they are a particular type of protein, which can cause disease. There is a mutation to the normal prion protein (PrPc) in FFI. This also means that there is a non-inherited sporadic form of the disease (sFI) where the gene may undergo mutation during life.
- Universally Fatal — death usually occurs within 18 months of diagnosis/symptom onset. Onset normally in middle age — mean age of onset is 50.
- Very rare — mercifully it has only been found in about 40 families worldwide, with an estimated 100 affected individuals but see my point below on potential misdiagnosis.
Precise Genetic Basis
If you are a genetics nerd the precise issue according to a paper by Schenkein et al  is:
“asparagine is substituted for aspartic acid at the 178 codon of the PrNP gene. Additionally, methionine (Met) occurs at codon 129 of the same mutated gene.[1,2] When methionine is also found at codon 129 of the non-mutated allele (Met-Met), the disease tends to run a shorter course than when the position is occupied by valine (Met-Val).”
The disease has been characterised by 4 stages and patients may present during any one of them, particularly since the disease is so rare and generally not well known.
It is likely that some cases may be misattributed as other types of dementia — particularly in the early stages.
Given the rareness of FFI vs other types of dementia this is not entirely surprising.
Some people may also die of other causes before the characteristic progression of the disease.
The Stages :
( as taken from Wikipedia as I could not access the original paper that reported them):
- Progressive Insomnia with associated anxiety, panic attacks, phobias and paranoia. Lasting about 4 months.
- Hallucinations and Panic Attacks Worsen lasting about 5 months.
- Complete Inability to Sleep with rapid weight loss — there is some dispute about how “complete” the inability to sleep is in different sources which is beyond the scope of this article. Suffice it to say the “normal” sleep becomes almost completely absent and this stage lasts about 3 months.
- Dementia — the patient becomes progressively less responsive, eventually mute. This is the terminal stage and lasts about 6 months.
N.B. — I have included these “stages” because a lot of the research alludes to them, however, I should point out that with a rare disease like this it hard to be certain if this is the actual progression.
Alternative Description by Schenkein et al.
In view of the above caveats I have found an alternative description from the 2006 Schenkein paper :
“The chief clinical features of FFI include a progressive and ferocious insomnia, waking “sleep,” hallucinations, autonomic disturbances suggestive of sympathetic overdrive (tachycardia, hypertension, hyperhidrosis, hyperthermia), a rise in circulating catecholamine levels, cognitive changes (such as attentional disturbance and short-term memory deficits without a loss in general intelligence), motor system deficits (ataxia), and endocrine manifestations. Later cognitive changes involve a confusional state resembling dementia and, ultimately, death.
The typical duration of FFI is between 7 and 36 months, with a mean duration of 18 months. Population studies show shorter mean survival time for Met-Met patients (12 ± 4 months) than for Met-Val patients, (21 ± 15 months).[3,9] These values are of particular relevance, because our case involves a Met-Met patient who surpassed 26 months of illness.
Clinically, 4 stages of FFI have been delineated, progressing from moderately disturbing to totally disabling. Although clinical symptomatology is related to polymorphism at codon 129, most end-stage patients are noninteractive and unable to care for themselves.”
What Causes the Damage in FFI?
This is an interesting question and not as easy to answer as it might first seem. There are a number of processes which may contribute:
- Lack of sleep may induce damage to the brain and body directly. It is known that complete insomnia is fatal within several days (in animal models).
- The abnormal prion protein seems to induce apoptosis (programmed cell death) within the brain though the precise mechanism for this is poorly understood. Certain areas such as the thalamus are more severely affected. Obviously this is going to affect brain function!
- There seems to be instability of the autonomic nervous system (the “autopilot” functions of your nervous system that keep you alive) and reduced activity in certain brain regions as result of damage/cell death noted above (e.g. thalamus). This in itself could potentially stress vital organs like the heart and kidneys due to fluctuations in heart rate, blood pressure etc.
- There are hormonal changes and disruption to normal “circadian” bodily rhythms which likely cause changes to the metabolism, immune function etc. This would also likely increase stress on the organs.
- Patient’s have been described as rapidly ageing as the disease progresses. This is likely an outward demonstration of the stress placed by these disruptions on the body.
It is likely that there is a combination of all the above factors leading to death.
It is interesting that people who carry FFI appear to be perfectly healthy until the presentation at middle age.
This would suggest that there needs to be some kind of triggering factor to cause the actual disease.
- This is initially clinical, based on a rapidly progressive cognitive impairment (dementia), behaviour or mood changes, ataxia (change to balance/coordination) with associated sleep disturbances.
- Sleep studies are usually performed next.
- Finally a PET scan (Positron Emission Tomography) is used to confirm thalamic hypometabolism (basically a part of the midbrain called the thalamus is less active than in normal subjects).
- Given the universally fatal nature of the disease genetic testing/counselling of carriers and relatives should be considered and handled very carefully. The gene variants themselves can be tested for and there is more information here.
Sadly right now there is no effective treatment. The main aim is to try to treat the symptoms and keep patients as comfortable as possible.
Conventional sleep drugs like benzodiazepines don’t seem to be useful.
There is limited evidence that more natural alternatives such as Gamma Hydroxybutyrate (GHB) may be useful.
This is interesting as GHB may naturally be involved in sleep regulation (and also growth hormone regulation) in the healthy brain.
It may be that FFI (at least partially) causes insomnia by a disruption to the normal levels of GHB. Sadly GHB was made illegal by most western governments due to the fear of abuse in the 1990s and early 2000s.
A prescription version of it is available in the US but obtaining it in other countries will likely be a problem as a result of this.
There is currently no way to stop the progression of the disease and eventual death of the patient.
There are anecdotal reports of various treatment plans improving quality of life and survival e.g. this Medscape Case Report but that is a single case and a sample of one is not compelling evidence.
The GARD (Genetic and Rare Diseases Information Center) discusses some preliminary research which may be of future interest:
“As of 2016, a number of treatments have had some success in slowing disease progression in animal models, including pentosan polysulfate, quinacrine (mepacrine), and amphotericin B. Sadly, the results have been less clear in clinical trials in humans. In Italy, a clinical trial trying to prevent symptoms in people known to have the genetic changes for FFI but have not yet developed symptoms is underway using doxycycline. Most promisingly, several forms of immunotherapy have reported success. The three main research areas focus on antibody vaccines, dendritic cell vaccines, and adoptive transfer of physiological prion protein-specific CD4+ T-lymphocytes. More research is being done to study how well these treatments work (effectiveness) and if the treatments are safe, but medical researchers believe that these or similar immunotherapies may offer hope for those with FFI in the future.”
Fatal Familial Insomnia is a truly horrendous disease which you would not wish on your worst enemy. The fact that you can’t even sleep properly (if at all) must make the situation all the more devastating.
One of the great mercies of this condition is that it is very rare, but that also means that it is much harder to study, slowing down progress towards effective treatments and more importantly a cure.
Thankfully there may be some hope from experimental immunological therapies.
For those who may be carriers or suffering from it this cannot come soon enough.
If you are interested in this subject then you may find these useful to watch. Obviously they may be quite distressing so please use caution if you are particularly sensitive.
- Schenkein, Joyce, and Pasquale Montagna. 2006. “Self Management of Fatal Familial Insomnia. Part 1: What Is FFI?” MedGenMed: Medscape General Medicine 8 (3): 65.
- Hauw, Jean-Jacques, Chantal Hausser-Hauw, Umberto De Girolami, Dominique Hasboun, and Danielle Seilhean. 2011. “Neuropathology of Sleep Disorders: A Review.” Journal of Neuropathology and Experimental Neurology 70 (4): 243–52.
- “Fatal Familial Insomnia | Genetic and Rare Diseases Information Center (GARD) — an NCATS Program.” 2017. Accessed January 14. https://rarediseases.info.nih.gov/diseases/6429/fatal-familial-insomnia.
- Mastrianni, James A. 2003. “Genetic Prion Diseases.” In GeneReviews(®), edited by Roberta A. Pagon, Margaret P. Adam, Holly H. Ardinger, Stephanie E. Wallace, Anne Amemiya, Lora J. H. Bean, Thomas D. Bird, et al. Seattle (WA): University of Washington, Seattle.
- “Fatal Familial Insomnia as a Sleep Disorder.” 2017. Accessed January 14. http://www.cureffi.org/2013/02/05/fatal-familial-insomnia-as-a-sleep-disorder/.
- Robson, David. 2017. “The Tragic Fate of the People Who Stop Sleeping.” Accessed January 14. http://www.bbc.com/future/story/20160118-the-tragic-fate-of-the-people-who-stop-sleeping.
- Calandra-Buonaura, Giovanna, Federica Provini, Pietro Guaraldi, Giuseppe Plazzi, and Pietro Cortelli. 2016. “Cardiovascular Autonomic Dysfunctions and Sleep Disorders.” Sleep Medicine Reviews 26 (April): 43–56.
Thank you for reading.
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